DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on Immunization Practices

February 21-22, 2007

Atlanta, Georgia

Record of the Proceedings

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION

ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES

February 21-22, 2007 

Atlanta, Georgia 

C O N T E N T S

February 21, 2007 

WELCOME AND INTRODUCTION.................................................................1 

 

HEPATITIS A POSTEXPOSURE PROPHYLAXIS ...............................................2 

 Introduction: Dr. Bell........................... .......................................................2 

 Study Results: Dr. Victor........................ ....................................................2 

 

ROTAVIRUS VACCINE ..............................................................................12 

General Update: Dr. Parashar......................................................................................13 

Disease Burden: Dr. Payne........................ .................................................14 

VAERS: Ms. Haber.....................................................................................................15 

Data Interpretation: Dr. Patel................... ...................................................16 

THIMEROSAL: REVIEWING THE EVIDENCE .................................................21 

Dr. Lieberman

VACCINE SUPPLY.....................................................................................28 

Dr. Wallace

INFLUENZA.............................................................................................32 

 Update: Dr. Allos..........................................................................................................33 

Information: Dr. Fiore...................................................................................................34 

 Vote...............................................................................................................................43 

 VFC Resolution: Dr. Calugar....................................................................................... 44 

Pandemic Vaccine Prioritization: Dr. Schwartz...........................................................45 

 FluMist Safety Data: Dr. Walker.................. ................................................49 

PUBLIC COMMENT...............................................................................................................41 

February 22, 2007 

UNFINISHED BUSINESS

 Dr. Abramson..................................... ........................................................55 

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DIPHTHERIA, TETANUS, PERTUSSIS, Hib, PENTACEL

 Dr. Joyce........................................ ..........................................................59 

IMMUNIZATION SAFETY OFFICE SURVEILLANCE UPDATES

 Dr. Davis........................................ ..........................................................60 

Dr. Iskander..................................................................................................................64 

HUMAN PAPILLOMAVIRUS VACCINE 

 Introduction: Dr. Gilsdorf....................... ...................................................68 

 Quadrivalent HPV Vaccine: Dr. Barr............... .............................................69 

Bivalent HPV Vaccine: Dr. Dubin............. .................................................73 

 Working Group Update: Dr. Markowitz.....................................................................79 

AGENCY UPDATES..............................................................................................................85 

CLOSING SESSION

ATTACHMENTS:

PARTICIPANTS ...............................................................................88 

ACRONYMS....................................................................................93 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

CENTERS FOR DISEASE CONTROL AND PREVENTION

ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES

February 21-22, 2007 

Atlanta, Georgia 

Minutes of the Meeting

The Department of Health and Human Services (HHS) and the Centers for Disease Control 

and Prevention (CDC) National Center for Immunization and Respiratory Diseases (NCIRD) 

[proposed] convened a meeting of the Advisory Committee on Immunization Practices 

(ACIP). The meeting was held on February 21-22, 2007 at CDC’s Global Communications 

Center, Building 19, in Atlanta, Georgia. The list of participants is appended to the minutes 

as Attachment 1. [Note: the list of participants only includes persons who introduced 

themselves for the record, presented, made public comments, or registered prior to the 

meeting.]

INTRODUCTION

At 8:11, Dr. Abramson welcomed everyone to the February 2007 ACIP meeting. Dr. 

Pickering introduced several international visitors, including Dr. Eibhlin Connolly and Dr. 

Jim Kiely from the Department of Health and Children in Dublin, Ireland, as well as Dr. 

Keiko Taya, Infectious Diseases Surveillance Center in Wakayama City, Japan, and Dr. 

Takehiro Togashi from Sapporo City University, Japan. He also introduced new 

representatives of ACIP liaison organizations. Dr. Tamara Lewis, American Health Insurance 

Plans replaces Dr. Andrea Gelzer. Dr. Stanley Grogg represents a new liaison organization: 

the American Osteopathic Association. Dr. Vesta Richardson from the National 

Immunization Council of Child Health Program in Mexico replaces Dr. Romeo Rodriquez. 

Dr. Harry Keyserling represents the Society for Healthcare Epidemiology of America. Dr. 

Geoff Evans (HRSA) was unable to attend the meeting, so Dr. Jevaji attended on Dr. Evans’ 

behalf. Dr. David Kimberlin from the American Academy of Pediatrics was also unable to

attend. Dr. Patricia Whitley-Williams from the National Medical Association also sent her 

regrets. 

Dr. Pickering noted that slide presentations would be posted on the ACIP Web site one to two 

weeks after the meeting. The ACIP home page is located at www.cdc.gov/nip/acip and is 

updated at frequent intervals to include meeting agendas, meeting minutes and presentations, 

ACIP recommendations, and other information related to immunization and ACIP activity. 

Dr. Pickering confirmed that there was a quorum of ACIP members present and explained 

that the ACIP charter gives the Executive Secretary or his or her designee the authority to 

temporarily designate the ex officio members as voting members if necessary. This would 

occur in the event that there are fewer than eight ACIP members available or who cannot vote 

because of conflicts of interest. The ex officio members will be formally requested to vote 

when necessary. If this occurs, they will be asked to express and disclose any potential 

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conflicts of interest. The goal in appointing members to the ACIP is to achieve the greatest 

level of expertise while minimizing the potential for actual or perceived conflicts of interest. 

The conflict of interest provisions state that members agree to forego participation in certain 

activities related to vaccines during their tenure on the committee. CDC has issued limited 

conflict of interest waivers for certain other interests that potentially enhance a member's 

expertise while serving on the committee. Members who conduct vaccine clinical trials or 

serve on data safety monitoring boards may serve as consultants to present to the committee 

on matters related to those vaccines. However, they are prohibited from participating in the 

deliberations or votes of the committee on issues related to those vaccines. Regarding other 

vaccines of an affected company, a member may participate in all discussions with the 

proviso that he or she abstains on all votes related to the vaccines of that company. All ACIP 

members must state their conflicts when they vote for a VFC resolution. ACIP members who 

may have a potential financial conflict of interest should make it known by disclosing all of 

their vaccine-related financial interests and work. 

 

Dr. Abramson asked ACIP members to state any conflicts of interest. Dr. Carol Baker stated 

she had a conflict with Novartis Vaccines. Dr. Janet Gilsdorf stated she was an independent 

safety monitor on an NIH-sponsored influenza trial, for which she receives no compensation. 

Dr. John Treanor said his group was involved in clinical trails of influenza or pneumococcal 

vaccines for sanofi, Protein Sciences, Wyeth, Novartis and Merck. Dr. Lieberman stated that

he was involved in clinical trials with Merck and MedImmune. Dr. Abramson stated that he 

served on a Data Safety Monitoring Board for an NIH-sponsored study of the use of 

oseltamivir in infants, and he received no compensation for this study. 

HEPATITIS A POSTEXPOSURE PROPHYLAXIS

Dr. Beth Bell, National Center for HIV, Hepatitis, STD and TB Prevention 

(NCHHSTP), CDC 

Dr. John Victor, PhD., Department of Epidemiology, School of Public Health, University 

of Michigan 

Dr. Bell explained the current ACIP recommendation with respect to hepatitis A postexposure prophylaxis calls for a single dose of IG as soon as possible but within two weeks of 

exposure; if hepatitis A vaccine also is recommended, it can be administered simultaneously 

with IG. The statement does address the question of the use of hepatitis A vaccine alone, 

saying results of an appropriately designed clinical trial comparing the post-exposure efficacy 

of vaccine with that of IG are needed to determine if hepatitis A vaccine without IG can be 

recommended. With this question in mind, about five years ago a trial was funded to compare 

the efficacy of hepatitis A vaccine to IG after exposure to hepatitis A virus, through a 

cooperative agreement with the University of Michigan’s School of Public Health. 

 

Dr. John Victor presented the results of that study. As background, he showed post-exposure 

efficacy estimates for IG from the published literature. Most of the studies were done before 

the advent of serologic tests. For the most part, these efficacy estimates were quite high and 

support the notion that IG is at least 85 percent effective for post-exposure prophylaxis. 

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Unlike most pre-exposure trials, in a post-exposure study potential participants must be 

ascertained within a relatively short time period after exposure, which is logistically difficult. 

Identification of cases and their contacts for potential post-exposure prophylaxis requires a 

site with relatively high endemicity and high rates of hepatitis A. 

 

The trial was conducted from October 2002 to April 2005 in Almaty, Kazakhstan, a very 

densely populated city of about 1.4 million people. Major hepatitis A outbreaks occur during 

the fall and winter periods and typically involve large numbers of young children. Over 95 

percent of recognized cases of hepatitis A are hospitalized. 

The study objective was to compare the efficacies of hepatitis A vaccine and IG in the 

prevention of laboratory-confirmed, symptomatic hepatitis A, when given within 14 days of 

exposure to a symptomatic index case. Eligible participants were household and day-care 

contacts of index cases identified from surveillance, ranging from 2 to 40 years of age. They 

had to be exposed to an index case within two weeks after index-case symptom onset, with no 

reported history of hepatitis A in the past and no receipt of hepatitis A vaccine or IG within 

the previous six months. Also, they had no reported medical diagnosis of chronic liver 

disease and no contraindications to either of the study interventions. The study interventions 

were hepatitis A vaccine, VAQTA, at the age-appropriate, licensed dose for pre-exposure 

protection and U.S.-manufactured IG at the standard post-exposure dust. Both interventions 

were administered intramuscularly in the deltoid in a scheme that maximized participant 

blinding. 

Within households and day-care groups, contacts were randomized at a 1-to-1 ratio to receive 

either intervention. Contacts were blinded to the intervention, but physicians administering 

the interventions obviously could not be blinded because of the different sorts of dosing. 

Therefore, physicians who had not administered the intervention, conducted the follow up and 

they were blinded. 

Susceptible contacts were followed weekly for eight weeks. At four and eight weeks post 

exposure, visits were made to interview contacts about hepatitis A-related symptoms and to 

collect further blood samples for testing. These visits coincided with the average and the end 

of the incubation period for hepatitis A. If there was serologic or biochemical evidence of 

infection or if a contact reported illness, a separate illness visit was triggered. Primary 

endpoints included illnesses occurring among contacts that met the following three criteria: 

positive for IgM anti-HAV; ALT level at least twice the upper limit of normal during an 

episode of illness with no other obvious cause; and one or more of the listed signs or 

symptoms of hepatitis A. 

Because the purpose of the study was to determine if hepatitis A vaccine is at least equivalent 

to IG, a noninferiority hypothesis was tested, stated as follows: Among those initially 

seronegative contacts who receive each intervention within 14 days of exposure to an index 

case of hepatitis A, the proportions of laboratory-confirmed symptomatic hepatitis A with 

onset between 15 and 56 days post exposure will be similar in the two intervention groups. 

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Similarity was defined as follows: assuming equivalence, one would expect to find a relative 

risk of 1.0, but one cannot test a statistical hypothesis and prove the null in the traditional 

sense. Instead, the statistical hypotheses were restated in terms of confidence-interval bounds 

around the point estimate. A null hypothesis that defined vaccine as substantially worse than 

IG was specified and rejection of the null would mean the two interventions were equivalent. 

“Substantially worse” was defined as a one-sided 95 percent confidence interval upper bound 

of the relative risk of 3.0. In order to reject the null and conclude similarity, the confidence 

interval bound on the observed relative risk was required to be less than 3.0. This 3.0 margin 

was selected in a pretrial meeting of experts in the clinical, epidemiological, and laboratory 

aspects of hepatitis A and in statistics and vaccine field-trial design, based on what was felt to 

be both clinically relevant and statistically valid. Assuming that IG efficacy would be 90 

percent, the confidence interval upper bound of 3.0 translates into a vaccine efficacy of at 

least 70 percent, so the vaccine efficacy estimate lower bound would be 70 percent. Although 

this confidence-interval bound defines the minimum vaccine efficacy, the point estimate of 

vaccine efficacy in this circumstance is greater than 84 percent. 

In exploratory secondary analyses, probable hepatitis A was examined, defined as any 

symptom plus serologic evidence of infection and biochemical or virologic evidence of 

infection, through PCR testing. The subset of cases that were icteric was examined, as well as 

subclinical illnesses that were confirmed by serology and by biochemical or virologic criteria 

but were asymptomatic. 

The results of the trial were as follows. During 29 months of enrollment, there were 4,524 

enrolled household and day-care contacts of 920 index cases of hepatitis A; 2,272 were 

randomized to vaccine and 2,252 received IG. Because about two-thirds were immune to 

hepatitis A from previous exposure in their lifetime, this left 740 susceptible persons who 

received vaccine and 674 who received IG. In this modified intent-to-treat data set, a little 

over half of contacts were female and about 85 percent were household contacts. Since over 

95 percent of primary endpoints and 98 percent of secondary endpoints observed in the study 

were among household contacts, there was actually very little day-care transmission. Both the 

index cases of contacts and the contacts themselves were on average relatively young, in early 

adolescence. Most contacts were immunized late in the two-week window of post-exposure 

prophylaxis. Over 86 percent received one of the study interventions in the second week post 

exposure. 

During follow up, 29 vaccine and 22 IG recipients were found with an illness confirmed by 

serology and ALT elevation. The independent data monitoring committee determined that 26 

vaccine and 18 IG cases actually met the criteria for primary endpoints. Most outcomes 

occurred during the second week of the post-exposure period. Illnesses occurred on average a 

few days earlier than the reported average incubation period for hepatitis A of 28 days, on 

days 24 and 25. There seemed to be a truncation of the incubation period since the latest case 

seen was at day 33 post exposure. The average age of cases among those who received 

vaccine was a bit lower than among IG recipients, though not statistically significant in the 

crude analysis. The peak ALT elevations measured at the time of illness among vaccine 

recipients were a bit higher than among IG recipients. Rates of PCR positivity, icteric illness, 

and frequency of gastrointestinal symptoms were similar in both groups. 

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In order to assure maximum robustness, the primary endpoint analysis was done on a perprotocol basis; for a non-inferiority study, it is important to remove all possible 

misclassification, since that biases toward the null. So 172 vaccine and 150 IG recipients 

were eliminated, leaving 568 vaccine recipients and 522 IG recipients. In the per-protocol 

data set, contacts had characteristics similar to those in the intent-to-treat analysis. 

For the primary endpoint, 25 cases of laboratory-confirmed hepatitis A occurred among 

vaccine recipients and 17 occurred among IG recipients, yielding a relative risk among 

vaccine versus IG of 1.35. That is the point estimate for the relative risk; the one-sided 95 

percent confidence interval upper bound of the relative risk was 2.4, which was well within 

the pre-specified margin of 3.0. The difference of the observed risks for the two groups was 

only 1.1 percent. So although vaccine might appear to perform slightly less well than IG, 

even though it met the criteria, the results show only a miniscule difference in the risk of 

hepatitis A in the two groups, especially compared to not treating at all. 

For the secondary endpoint of icteric illness, a similar point estimate was found for the 

relative risk; even though the confidence interval upper bound is slightly higher, there were 

fewer cases that were icteric. Looking at all clinical and subclinical infections together, both 

the confidence interval and the point estimate are less than a relative risk of 2.0. Most cases 

were among children in the study, so that is where most of the inference was made. However, 

no major differences appear in estimates for adults. 

Dr. Victor then put the relative-risk results in context and described implications for vaccine 

efficacy. The assumption of 90 percent IG efficacy implied an underlying secondary attack 

rate of 33 percent in the study population. If this assumption was correct, the study results 

would translate into a point estimate of vaccine efficacy of 86 percent and the lower bound of 

the 95 percent confidence interval would have been 76 percent. Therefore one can be quite 

confident that vaccine efficacy is high in this situation. Using a slightly lower secondary 

attack rate, the estimate of vaccine efficacy is still very good. 

In summary, the efficacy of vaccine post exposure appears quite high and similar to that of 

IG. The risk of hepatitis A for vaccine recipients was never more than 1.5 percent greater 

than the risk for IG recipients for any of the endpoints looked at. There is some evidence that 

IG may be attenuating clinical illness based on the characteristics of the cases seen. There 

was no evidence that vaccine given in the second week after exposure resulted in lower 

clinical protection. Finally, contacts in households experienced the highest transmission rates 

in the study. 

Dr. Bell provided some additional data and talked about potential implications. The question 

before the committee has to do with using hepatitis A vaccine alone post exposure. There are 

a number of potential benefits of being able to use vaccine, including long-term protection, 

ease of administration, acceptability, and availability. In addition, there is currently only one 

U.S. supplier of immune globulin and the cost has risen considerably over the last five or ten 

years, making it similar to that of hepatitis A vaccine. A single adult dose of IG now is about 

$20, a pediatric vaccine dose under government contract is about $12, and an adult dose is 

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about $19. Another benefit of being able use hepatitis A vaccine is that it brings U.S. practice 

in line with many other countries that recommend vaccine as post-exposure prophylaxis. 

Only one other clinical trial used hepatitis A vaccine post exposure and that was conducted in 

Italy in 1997. This study enrolled 212 household contacts, aged 1 to 40 years, of hospitalized 

hepatitis A cases. Contacts were randomized to receive either the GSK vaccine within eight 

days of symptom onset of the index case or no intervention. The outcome was IgM positivity 

as measured either at Day 14 or Day 45 post vaccination or post no intervention. The trial 

was stopped when the study results reached statistical significance. The estimated vaccine 

efficacy was 79 percent, with a very wide confidence interval. The outcomes identified 

included two in the vaccinated group, ages 10 and 11 years, both of whom were asymptomatic 

with normal ALTs. Since vaccination can induce IgM, it is possible that these two so-called 

vaccine failures, in fact, did not have hepatitis A. In the no-intervention group, there were 12 

outcomes, aged 3 to 25 years, the majority with symptomatic hepatitis A and elevated ALTs. 

This study was of limited usefulness in the U.S., where there was already an efficacious 

intervention in IG, but it did provide good evidence that the vaccine did a reasonable job of 

preventing hepatitis A. 

Unfortunately, results of the current study and previous information cannot answer all 

questions about how hepatitis A vaccine performs post exposure. Eligibility was restricted to

age 40 and under in the Kazakhstan study. Most cases and study participants were fairly 

young, which is not surprising, given that essentially all adults older than 40 are immune to 

hepatitis A, as are many younger adults. Patients who reported a diagnosis of chronic liver 

disease were excluded, based on concern about the increased severity of hepatitis A in those 

people. People with other medical conditions were not explicitly excluded, but in general, the 

study population was young and healthy. 

Only one of the two U.S.-licensed vaccines was used, so there is the question of the 

generalizability of the findings to both licensed vaccines. There is also the question of time 

since exposure. Going into the study, many might have thought that vaccine would not 

perform as well in the second week after exposure. Any recommendation the committee 

might make about the ability to use vaccine would represent off-label use because the 

manufacturers do not intend to apply to FDA for this as an indication. Finally, it is likely that 

currently available data are all that will be available. Additional studies addressing these 

areas with limited data are logistically unfeasible. 

Dr. Bell shared some technical information about the antibody to hepatitis A virus. The 

minimum protective antibody concentration is unknown, and in fact, it may be below the 

assay-detection limit. For example, after IG administration, it is known that protection 

continues after antibody is no longer detectable. In vaccine immunogenicity studies, 

protection has been defined as the lower limit of detection of whatever assay was being used. 

This can vary from 10 to 33 mIU per ml, which complicates the precision with which one can 

look at the available pre-exposure immunogenicity data. 

With that caveat, Dr. Bell presented a summary of data available from the pre-exposure 

studies about seroconversion after one dose of hepatitis A vaccine, which seem to be most 

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relevant to how hepatitis A vaccine might perform post exposure. Ninety-five percent or more 

of children seroconvert by four weeks after the first dose. However, many of these studies 

were conducted using old formulations of the vaccine, which was a three-dose series, with the 

first dose being half of the currently licensed dose. That makes it very difficult to study 

response after one dose of what is used now. Thus there are no published data among 

children that report seroconversion at two weeks. The GSK package insert reports that 92 to 

96 percent of children have seroconverted at two weeks, citing unpublished data. 

Essentially all adults (over 18 years old) seroconvert by four weeks. Using the currently 

licensed formulations, one or two published studies and information in the package inserts 

quote anywhere from 70 percent to 100 percent seroconversion at two weeks after one dose. 

Only one published study was found that directly compares the response after a single dose of 

vaccine in younger versus older adults, and that study used the currently licensed formulation 

of the GSK vaccine. At Day 15, the study reported 90 percent seroconversion among younger 

adults versus 77 percent among older adults, and by one month, 97 percent were seropositive 

in both groups. 

 

Data from the National Health and Nutrition Examination Survey conducted in 1988 to 1994 

address the likelihood of adults and older adults in the United States being susceptible to 

hepatitis A. About 50 percent of 40- to 49-year-olds are immune, rising to 60 to 65 percent in 

older adults and reaching over 70 percent in adults age 70 or older. It is reasonable to 

conclude that the majority of adults remain susceptible to hepatitis A in the U.S. 

The next issue addressed was the response to hepatitis A vaccine among people with medical 

conditions and immunocompromised people. The data are fairly limited with respect to 

response after one dose of vaccine and there are no data regarding response at two weeks; all 

the data are at four weeks. Among HIV-infected patients, the three relevant studies report a 

wide range of seroconversion after one dose, ranging from 10 to 78 percent. The percent 

positive is higher with a higher CD4 cell count, but in several studies a much lower than the 

usual 95 percent of adults seroconvert after one dose. Hepatitis A vaccination is 

recommended for patients with chronic liver disease, so there has been a fair amount of 

interest in studying the immunogenicity of the vaccine in these patients. In the three 

published studies, the percent positive at four weeks ranges from 63 to 93 percent. In the one 

study that used a control group, the percent positive was lower than controls. It appears that 

the response rate is lowest in patients with decompensated cirrhosis. Finally, a few studies in 

liver and kidney transplantation patients show a much lower percent positive at four weeks. 

Dr. Bell mentioned two other considerations. The first was time since exposure. The Italian 

study cut off at seven days post exposure. The current study appears to remove theoretical 

concern about diminished vaccine efficacy with longer time since exposure; there was no 

difference between the groups in time since exposure, and most interventions were given 

fairly late in this two-week post-exposure limit. A second question is the comparability of the 

two U.S.-licensed vaccines. They are considered equivalent for pre-exposure use but there 

have been very few head-to-head comparisons. Because of problems with the different 

assays, it is difficult to make precise comparisons but the percent seroconverting appears to be 

similar.

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Many other industrialized countries that recommend post-exposure prophylaxis have 

recommendations for using vaccine. In Canada, since 2000 the recommendation has been that 

vaccine without IG is preferred during the first 7 days after exposure, with a recommendation 

of IG for infants and immunocompromised persons. Apparently IG is more difficult to get in 

Canada than in the U.S. In the U.K., since 2001 the recommendation has been to use vaccine 

if the exposure has been within the previous seven days, based on the Italian study, and to 

continue to use IG if the exposure has occurred more than seven days previously and for 

people older than 50 years, cirrhotics, and people with chronic viral hepatitis. During 2000-

2003, a survey was conducted of European countries with respect to viral hepatitis. France, 

Italy, and Belgium all reported using vaccine only for post-exposure prophylaxis. Only 

Sweden and perhaps Norway reported using only IG for post-exposure prophylaxis. The 

majority of the other countries used vaccine or vaccine and IG. 

Dr. Bell then described the current epidemiology of hepatitis A in the United States. The 

provisional total number of cases in 2006 was about 3300, compared to 20,000 - 35,000 

hepatitis A per year during the past several decades. Although communitywide outbreaks do 

occur not anymore, vaccine has been recommended in that context for the past decade. The 

common setting for IG use as post-exposure prophylaxis currently is among household and 

other close personal contacts. Outbreaks in childcare centers used to often require IG, but 

now these outbreaks are rare. 

It is difficult to quantify exposure from an infected food handler, but surveillance data 

indicate that 3 to 7 percent of reported hepatitis A cases are food handlers. A study funded a 

few years ago in a couple of states found that about 5 percent of food handlers worked while 

they were infectious and were felt to pose a transmission risk. In the context of contact 

notifications, an average of 350 IG doses per episode were administered. Health departments 

do not systematically keep track of how much IG has been used such settings, but given the 

low number of cases these days, it is potentially on the order of tens of thousands of doses and 

not likely more than 100,000. 

In summary, vaccine offers a number of advantages over IG, and the flexibility to use vaccine 

in some circumstances would be beneficial. The available data suggest that vaccine is 

efficacious post exposure, but not all populations were studied. The relevance of preexposure immunogenicity data is unclear and they do not suggest large differences in 

responses of children and healthy adults to vaccine. Some adults might not respond as 

briskly, but the clinical significance of this finding is quite unclear. It does appear that there 

are suboptimal responses at least in some immunocompromised persons. Since additional 

data are not likely to be forthcoming, the committee needs to balance the practical public 

health implementation considerations against the limitations of the available information. 

 

Discussion

Dr. Bell read the two paragraphs the committee was considering: "Persons who recently have 

been exposed to HAV and who previously have not received hepatitis A vaccine should be 

administered a single dose of IG as soon as possible." She explained that this was the 

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wording of the current statement and the proposal was to add the following: "Based on limited 

data showing equivalent efficacy to IG, hepatitis A vaccine at the age-appropriate dose 

licensed for pre-exposure use can be used instead of IG. The efficacy of IG or vaccine, when 

administered more than two weeks after exposure has not been established. For persons who 

receive vaccine the second dose should be administered according to the licensed schedule to 

complete the series." 

The second paragraph read, "IG should be used for children less than 12 months old, 

immunocompromised persons, and persons for whom vaccine is contraindicated. The 

postexposure efficacy of hepatitis A vaccine in persons younger than two or older than 40 

years old and persons with chronic liver disease or other medical conditions has not been 

studied. Persons who have been administered one dose of hepatitis A vaccine more than two 

weeks before exposure to HAV do not need IG." 

Dr. Allos asked whether it was correct to say that there was no greater risk of developing one 

of the endpoints or increased LFTs if either the IG or the vaccine was received later in that 

two-week interval. Dr. Victor replied that he categorized time of receipt as either within the 

first week or second week and then also looked at it on a continuous scale. Most of outcomes 

occurred the second week after exposure and there was no difference between vaccine and IG 

in that context. Dr. Allos then asked for clarification of the phrase “it hasn't been studied” in 

the recommendation. The presentation suggested there were immunologic data available for 

people with HIV and liver disease. Dr. Bell explained that the post-exposure efficacy has not 

been studied, and that the data shown were immunogenicity when the vaccine was given preexposure. 

 

Dr. Treanor asked why, if the hepatitis A is a neoantigen in a susceptible person, the response 

was so rapid to a single dose. Dr. Bell replied that she wasn’t sure anyone knew the answer, 

but it was consistently the case. In some of the very early studies where a modified IgM assay 

was used, which was much more sensitive than the usual IgM assay, one could see IGM 

coming up even sooner. Dr. Treanor responded that if these rapid responses occured because 

people are somewhat primed by exposure to other enteroviruses, then one might see a 

difference between the kinetics of the antibody response in a population like Kazakhstan and 

the U.S. population. He wondered whether children in Kazakhstan respond more rapidly to a 

single dose of hepatitis A vaccine than children in the U.S., where perhaps background rates 

of enterovirus infections might be lower or where there's a much lower rate of background 

hepatitis A transmission. Dr. Bell replied that all the pre-exposure immunogenicity data 

shown were U.S. data. 

Dr. Baker noted that a public health conclusion for the comments about outbreaks in the U.S. 

is that all food handlers should be immunized, and wondered if any thought had been given to 

that strategy. Dr. Bell said there was no objection to vaccinating food handlers. Restaurants 

should be reminded that often food handlers do have other indications for vaccination. When 

this question has been studied from an economic point of view, it has never appeared to be a 

favorable policy largely because of the turnover among food handlers. In fact, as hepatitis A 

vaccine was about to be licensed, a number of the large restaurant chains appeared to be 

interested. While a few have adopted it, not as many as might be expected have done so, 

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probably because of staff turnover. Dr. Baker then asked why everyone with hepatitis was 

hospitalized in Kazakhstan. Dr. Victor replied that this was a lingering practice from the 

Soviet Union era. 

 

Dr. Kathy Neuzil asked whether the concentration of specific IgG or antibody against 

hepatitis A in commercial IG preparations was changing over time. Dr. Bell responded that 

the concentration of anti-HAV in commercial IG preparations is not routinely measured. 

There has been some theoretical concern that perhaps the antibody concentrations have been 

falling in IG, but no clinical evidence that the efficacy of IG has changed. 

 

Dr. Dale Morse wondered if the FDA had any comments. Dr. Baylor responded that one of 

the downsides was that it is an off-label use. The limitations of the data presented are 

indicative of the fact that this would not support an indication alone. However, the FDA 

recognizes that flexibility needs to be written in. 

Dr. Ciro Sumaya asked what the basis was for the U.K. recommendation for IG. One of the 

slides seemed to indicate that if the post-exposure period is greater than seven days, then the 

recommendation is for IG rather than vaccine. Dr. Bell replied that, according to the Dr. 

Crowcroft in the U.K., the reason was that the Italian study cut off at seven days, so there 

were no data past that. She suspected there was concern that vaccine did not work as well in 

the second week after exposure. Dr. Crowcroft thinks the actual practice is quite variable in 

the U.K. and they do continue to distribute a fair amount of IG. Dr. David Salisbury added 

that the updated guidance issued at the beginning of this year had not changed this part of the 

hepatitis A guidance. It still says to use a one-week cutoff, based on all the evidence available 

at the end of last year. However it does say that the HNIG that should have an antibody level 

of at least 100 IU per ml. 

 

Dr. Treanor referred to the fact that the vaccine is the primary prophylaxis mode for many 

countries and wondered if there was information about the rate with which that prophylaxis 

fails in countries that use it routinely. Dr. Bell responded that the U.K. only had 700 or 800 

hepatitis A cases a year, which would not yield much information about failures. In Canada 

much of the vaccine has been used in outbreak settings, for which vaccine is already 

recommended. Dr. Naus added that there was information about one situation in Canada in a 

school and some additional cases in a day-nursery setting, where there were a number of 

failures among children who had received the vaccine. Canadian guidelines were also based 

on the Italian study. While Canada has a permissive recommendation about administration of 

IG more than seven days out from exposure, there is probably very little IG use now because 

of the preferential statement to administer vaccine. 

 

Dr. Bill Schaffner asked about the availability of IG. Dr. Bell replied that Bayer, the one 

manufacturer, was continuing to make IG. There is another market for IMIG in this country, 

which may be larger than the public health market. Some patients with immune deficiency 

apparently use large volumes of IMIG. She didn’t believe Bayer's production schedule had 

recently been interrupted, but since this is a shrinking market, the distribution may be 

somewhat spotty. 

 

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11

Dr. Neil Halsey from Johns Hopkins had two comments. First, the wording of this statement 

strongly implies a preference for IG, but the data do not support such a preference, especially 

in the first week. He felt the two sentences should be combined, indicating that either can be 

used and the committee should decide whether there would be a preference. Second, the 

guidelines for pre-exposure prophylaxis for travelers need to be revised. To best of his 

knowledge, travel clinics are just about only using vaccine and ACIP guidelines are out of 

touch. Dr. Bell responded that in the most recent statement, the wording in terms of travelers 

is much more permissive, downplays IG, and has shortened the recommended time interval. 

Dr. Halsey indicated that for pre-exposure, only vaccine is needed, while the guidance still 

implies the need for immune globulin. 

 

Dr. Harry Keyserling asked whether it would be appropriate to have a special category with 

higher standards for healthcare workers, since the implications of infection and transmission 

are compromised and should be different. Dr. Bell thought the need for prophylaxis after 

exposure to hepatitis A in hospitals was extremely unusual. Dr. Keyserling said that was true 

for exposure in hospitals from patients, but it would more likely be exposure within families, 

which a healthcare worker would report to employee health. 

 

Dr. John Temte, American Academy of Family Physicians, wondered if there was any sense 

about the distribution between rural and urban areas in terms of the required use of 

prophylaxis. Dr. Bell said in the old days, the large communitywide outbreaks of hepatitis A 

often occurred in urban areas, so the need for post-exposure prophylaxis after household 

contact was probably greater in urban areas. These days, without those communitywide 

outbreaks, there’s probably no difference between those two settings. 

 

Dr. Jeff Duchin from NACCHO asked about the implications of the trend towards younger 

children in both of those groups, and whether that would have been significant if this study 

was larger. Perhaps transmission is more likely among younger people and they were 

overrepresented in the vaccine group. Dr. Victor said that was possibly the case. In a pilot 

transmission study conducted the season before this study was implemented, secondary attack 

rates in the age group from zero to six years were about 35 to 40 percent, compared to adults, 

where they were under 20 percent. 

 

Dr. Barbara Kuter from Merck added some information to the immunogenicity data 

presented. First, to address the question about the use of the vaccine in individuals less than 

40 versus greater than 40 years of age, particularly for healthcare workers, there are data 

suggesting that the 50-unit dose of VAQTA has a pretty flat response across all age ranges. 

Also, regarding the kinetics of response, Joe Bryan from the U.S. military did a randomized 

cross-over study between the two available vaccines. That paper pointed out some 

differences in the kinetics of response, particularly at the early time points of two and four 

weeks, and some differences with regard to the levels of antibody obtained between the two 

vaccines. 

Dr. Pickering asked whether the ACIP members were ready to vote on the general 

recommendation as presented, or did they still have questions about specific aspects of the 

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12

recommendation. There would be a chance to look at the manuscript produced, with more 

detail about specific subgroups. 

 

Dr. Kathy Neuzil said she preferred something in between, based on what Dr. Bell had said 

about giving the two [vaccine and IG] together. Dr. Bell reiterated that the current 

recommendation was that the two can be given together if there is an indication -- a preexposure indication for vaccine. In other words, if someone is seen post exposure, give them 

IG, and if there is a reason to give them vaccine as well, that ability already exists. The 

question is whether there are any circumstances in which IG does not have to be given post 

exposure. 

Dr. Dale Morse agreed that there were a number of nuances to consider and his preference 

was to discuss them before voting. If the paper hasn't been published and discussed in the 

literature yet, he wondered why the recommendation was coming forward for a vote. Dr. Bell

replied that the abstract and tables were among the materials that the committee received 

ahead of time. 

Dr. Abramson said he sensed that a number of people were still trying to deal with specific 

groups, such as the immunocompromised and people with chronic underlying disease. He 

suggested sending something out to ACIP for comment and bringing it back at the June 

meeting. Dr. Treanor added that, ultimately, the committee would probably approve the 

general principle of using the vaccine, the only issue being whether there should be a specific 

list of people that should get IG instead. 

 

Dr. Abramson asked whether the committee was willing to approve the overall principle, i.e., 

vaccination as a main means of prophylaxis and then take on the nuances about the specific 

subgroups. Dr. Treanor said he wished there was more information about how this strategy 

has worked in other countries. Hearing that there may have been failures in Canada is 

unsettling, but basically the data would support the recommendation without having to look at 

every single set of conditions before voting. 

Dr. Neuzil felt the recommendation could be interpreted as saying vaccine is inferior. She 

was comfortable with vaccine recommendation from the data presented, and the other 

advantages of vaccine, such as the simplicity and the long-term protection that IG does not 

provide, but the language needs editing. 

Dr. Lieu felt the issue of whether IG is preferred to vaccine or whether vaccine is considered 

equivalent to IG really needed to be part of the vote. Dr. Baker suggested delaying the vote 

just to edit the one sentence that implies an either/or rather than a preferred recommendation. 

Dr. Greg Wallace, CDC, reminded the committee that the specific language has to be agreed 

upon before the VFC vote. The decision was to return to the issue the next morning and make 

a decision then. 

ROTAVIRUS VACCINE

Update on U.S. Rotavirus Vaccination Program 

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13

Dr. Umesh Parashar, National Center for Immunization and Respiratory Diseases 

(NCIRD)

Dr. Parashar reviewed a number of key milestones that had occurred during the previous 

calendar year. About a year ago, the U.S. FDA licensed Rotavirus Vaccine, Live, Oral, 

Pentavalent (RotaTeq®), which was subsequently recommended for routine immunization of 

all U.S. children. 

Another vaccine, Rotavirus Vaccine, live attenuated (Rotarix), made by GlaxoSmithKline, 

has not yet been submitted to the FDA for U.S. licensure, but has been licensed in more than 

70 other countries, including those in the European Union. A large clinical trial was done and 

the vaccine has now been introduced into immunization programs in several Latin American 

countries, including Brazil, Panama, Venezuela, and El Salvador. 

In November of 2006, the Global Alliance for Vaccines and Immunization approved the 

investment case for purchase of rotavirus vaccines for use in the public sector in GAVIeligible countries, which are countries below an income cutoff of $1,000 GNP per capita. The 

initial investment case signaled approval for purchase of the vaccine for GAVI-eligible 

countries in Latin America and Eastern Europe. Clinical trials of both vaccines are ongoing 

or soon to start in Africa and Asia, and only when those data become available will a broader 

recommendation be issued. 

RotaTeq is a reassortant vaccine made by Merck. By genetic reassortment, human antigens 

have been introduced into a bovine strain. There are five reassortants included in the vaccine 

against G1, 2, 3, 4, and P8, and these are essentially the GNP types of 80 to 90 percent of 

strains in the U.S. It is a liquid preparation given directly to the infant by mouth in three 

doses, and recommended at two, four, and six months of age routinely. 

Data from the large vaccine effectiveness trial indicate that RotaTeq is highly efficacious 

against hospitalizations, emergency-department visits, and office visits for rotavirus 

gastroenteritis. Rate reductions range from 96 percent against hospitalizations to about 85 

percent for office visits. The trial enrolled about 70,000 infants, and was designed to look at 

intussusception, an adverse event associated with a different rotavirus vaccine used in the U.S 

seven years ago. The data include cases of intussusception, broken down for each of the three 

doses. The primary safety endpoint was cases of confirmed intussusception within 42 days of 

any dose. There were a total of six cases of intussusception in vaccine recipients and five in 

placebo recipients. The relative risk, not adjusted for the multiple comparisons made, was 

about 1.2, indicating no evidence of any association of this vaccine with intussusception. 

RotaTeq has now been licensed in Europe, Australia, Canada, and many other locations. 

Outside the U.S., the largest user in the public sector is in Nicaragua, where a demonstration 

project was launched in October 2006 for routine immunization of all infants in that country. 

The vaccine is being donated by the manufacturer for a period of three years for the entire 

birth cohort. 

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14

Rotarix, the vaccine made by GlaxoSmithKline, has been tested in a similar large trial. This 

vaccine is based on a single strain of Serotype G1P[8] rotavirus, a human strain that is, by far, 

the most common single strain globally. In the past 10 years, about 60-80 percent of rotavirus 

strains seen in hospitalized children are of this serotype. It's a lyophilized product, given by 

mouth in two doses after reconstitution with a buffer preparation. When this vaccine was 

tested in a large efficacy trial, primarily in Latin America, it showed about 85 percent efficacy 

against severe rotavirus disease and disease leading to hospitalizations. This trial was also 

large enough to look at the risk of intussusception. Over 30,000 infants got vaccine and 

placebo. There were six cases of intussusception in vaccine recipients and seven in placebo, 

with a relative risk lower than one. For both Dose 1 and Dose 2, there was no excess of 

intussusception in the vaccinated groups. This vaccine may be submitted to the FDA for 

licensure sometime in the future.

Rotavirus kills more than half a million children globally each year. In the U.S., there are few 

deaths, but a large number of hospitalizations and other severe health outcomes. The vaccine 

looks promising for prevention of severe disease and deaths in developing countries. 

Update on Rotavirus Disease Burden and Vaccine Effectiveness Monitoring 

Dr. Daniel Payne, National Center for Immunizations and Respiratory Diseases 

(NCIRD)

The New Vaccine Surveillance Network (NVSN) is a prospective, population-based, acute 

gastroenteritis surveillance platform for three U.S. counties. Another wing of the NVSN is 

the acute respiratory illness (ARI) platform. The three counties are Davidson County, 

Tennessee (surveillance conducted by Vanderbilt University), Monroe County, New York 

(University of Rochester), and Hamilton County, Ohio, (Cincinnati Children's Hospital 

Medical Center). The epidemiological data collected include parental interviews; medicalchart reviews; clinical outcomes from inpatient, emergency-department (ED), and outpatientclinic visits; and laboratory data. Enzyme immunoassays (EIA) are performed at the hospital, 

and rotavirus-positive-by-EIA samples are sent to CDC for further typing. 

The objective of acute gastroenteritis and rotavirus surveillance is to directly estimate the 

annual burden of rotavirus gastroenteritis among children under three years old in the three 

counties, and to monitor the effectiveness and impact of rotavirus vaccination. The data 

presented were from surveillance conducted between January 1 and June 30, 2006. 

Dr. Payne showed a chart that described the curve for rotavirus cases. February, March, and 

April accounted for a substantial amount of the AGE cases captured among less than threeyear-olds. Forty-four percent of all of AGE cases under three years old were found to be 

rotavirus positive by EIA. They were fairly consistent statistically across the three 

surveillance sites. Another stratification of percent rotavirus-positive by EIA is by provider 

type – hospital, emergency department and outpatient clinic. The hospital and ED percent 

rotavirus-positive is 50 percent, which is on the higher edge of what would have been 

expected from previous publications, and about one-quarter of outpatient clinic AGE cases 

were rotavirus-positive during this season. 

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15

 Rotavirus burden was calculated and adjusted for differential specimen collection and 

differential enrollment practices. The 2000 census data were used as a denominator. For 

children under three years old (rates per 10,000 children), some site variability in 

hospitalization rates is seen, but the aggregate total rate is 28.9 rotavirus hospitalizations per 

10,000 children in these counties. This matches very well with some of the published 

estimates that use indirect methods, in particular, the National Hospital Discharge Survey of 

rotavirus hospitalizations under five, which was 27.4 per 10,000. Although 28.9 per 10,000 is 

an aggregate, the burden of this disease falls very heavily upon the February, March, and 

April months of the year. Looking at hospitalization among under-three-year-olds by month, 

one can see that in March, for instance, the rotavirus AGE burden is approximately six times 

that for all other pathogens combined. 

All EIA-positive rotavirus samples are sent to CDC, where they are tested for strain types. 

The G[1]P[8]strain is most common, about 80 percent, as expected. No G3 or G4 strains 

were found, and the G9-strain proportion was a bit lower than would have been expected from 

previous published reports. Interestingly, the G[12]P[6] strain was found in over 3 percent of 

the sample, which will be watched carefully in future surveillance.

 One objective of the NVSN rotavirus effectiveness studies is to determine post-marketing 

vaccine effectiveness in the three NVSN communities. Cases will be collected during the 

2007 rotavirus season, as well as the following season. Two different control methods will be 

used: community cohorts and comparison with other NVSN surveillance controls based on 

vaccination status. In the current data there were no vaccinees, since the vaccine was only 

licensed in February 2006. 

A limitation of the study is that several untypables or mixed-strain specimens were found, 

which are being further analyzed by CDC. Also, one year of surveillance data places limits 

on conclusions because of the very small n, but further surveillance years should help to 

verify some of the specific trends. 

 In conclusion, the rates of rotavirus hospitalizations found are fairly consistent with published 

estimates and those previously presented to the committee. But 2006 appears to have been a 

mild rotavirus season in the Rochester, New York area. Half of the acute gastroenteritis 

hospital and emergency-department visits were for rotavirus. This was consistent across sites, 

but a little higher than expected. Approximately 96 percent of the strains detected had 

matching antigens covered by the current rotavirus vaccine. Results show the strength of the 

NVSN platform to monitor trends of rotavirus burden, strain prevalence, and also vaccine 

effectiveness in upcoming years. 

Summary of RotaTeq Vaccine Reports to VAERS 

Ms. Penina Haber, CDC Immunization Safety Office 

Dr. Manish Patel, National Center for Immunizations and Respiratory Diseases 

Since March 2006, about 3.6 million doses of RotaTeq vaccine have been distributed in the 

United States. From March 1, 2006 to February 15, 2007, VAERS received a total of 567 

reports pertaining to any RotaTeq vaccination. Of those, 51 percent were after RotaTeq 

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16

vaccine alone and 57 percent were after Dose 1. Most frequently reported adverse events 

were diarrhea and vomiting. 

Looking at onset interval in days, about 50 percent of reports were between zero to two days 

and over 30 percent did not have information about the onset interval. As of February 15th, 35 

reports of IS have been confirmed. Of those, 17 were 1 to 21 days post vaccination and 11 of 

those were one to seven days. No deaths were reported. Reports of onset interval ranged as 

high as 73 days. Between two and six days post vaccination, there are 11 reports. 

 

For the 17 reports of intussusception by Dose 1 and Dose 2 from onset interval Day 1 to Day 

21, there were nine reports for Dose 1, and of those, seven were between two and six days. 

For Dose 2, there are eight reports, including one on Day 0, the day of vaccination. No cases 

were reported after dose 3 within 1 to 21 days. Overall, the mean and median age of symptom 

onset was 21 and 20 weeks, and the range was 10 to 37 weeks. Forty-three percent of reports 

were male, though gender was not reported in 11. Of the 17 reports within 1-21 days of 

RotaTeq vaccination, five had surgical reduction and another five had surgical resection. Six 

percent of the 17 reports within 1-21 days had contrast enema reduction. 

Lab results from tissue or stool or both specimens have been very limited. Of the reports 

within 1-21 days, 4 were tested and none was positive for rotavirus or adenovirus, which is 

known to be associated with intussusception. One stool sample tested positive for vaccine 

strain at Day 6, which is expected after RotaTeq administration. 

Data from the VSD study show that, as of February 14, 2007, 28,377 children were 

vaccinated, which included six out of eight sites of the participating study of the VSD. No 

intussusception report within 30 days was found following RotaTeq vaccination. Data on 

uptake by age group in weeks and dose number show that about 61 percent of the vaccination 

went to Dose 1, 30 percent to Dose 2, and 9 percent to Dose 3. 

The Merck Phase IV study is a prospective review of the original active surveillance. The 

study population is a large insured population in the U.S., with an annual birth cohort of about 

100,000 a year. The planned study size will be 44,000 vaccinated children. Rates of 

intussusception and overall vaccine safety will be monitored and compared with rates in 

several control groups. The study period will be 30 days post vaccination for each dose. So 

far, 1,354 RotaTeq recipients were followed up through September 30, 2006, and no case of 

intussusception was found. Over 16,000 first-dose vaccinees were enrolled by December 

2006, and those data are currently being evaluated. 

 

Interpretation of the Data 

The primary question to be addressed is whether the observed number of intussusception 

reports to VAERS exceeds the expected number of cases likely to occur by chance alone. To 

calculate the expected rates of intussusception, two key data elements are necessary: the agestratified baseline rate of intussusception, and the number of vaccine doses administered and 

the age at which these doses were administered. 

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17

Regardless of the data source, intussusception rates increase several-fold during the first six 

months of life, illustrating the importance of age-adjusted analysis. Data from the Healthcare 

Utilization Project, or HCUP, captures about 85 percent of national inpatient hospitalizations. 

Looking at annual background intussusception rates per hundred thousand for the years 1993 

through 2004, it can be seen that the rates increase dramatically between birth and 24 weeks 

of age. However, rates may vary depending on the data source. Background rates of data 

from the Vaccine Safety Datalink (VSD) and the Healthcare Utilization Project (HCUP), rates 

appear to be reasonably similar. The calculations presented used VSD background rates, as 

VSD is a robust source of data. Rates were also categorized by age of onset: 6 to 14 weeks, 

15 to 23 weeks, and 24 to 35 weeks. The background incidence of intussusception varies 

dramatically between these age groups and the three-dose RotaTeq series is being 

administered according to this schedule, which is close to the ACIP-recommended schedule. 

The second important data element for calculating expected rates is the number of doses 

administered. Although the exact number of doses administered to date is unknown, 

approximately 3.6 million doses were distributed by the manufacturer through the end of 

January 2007. Of the 28,000 doses of vaccine administered within VSD, 57 percent were 

given to infants 6 to 14 weeks of age, 31 percent were given to infants 15 to 23 weeks of age, 

and 12 percent administered to infants 24 to 35 weeks of age. These proportions are similar to 

the proportion of Doses 1, 2, and 3 that were administered within VSD. So in essence, the 

calculations presented by age throughout the rest of the presentation are similar to the 

calculations by dose. 

Two time windows of potential intussusception risk after RotaTeq vaccination were used: 1 to 

21 days and 1 to 7 days after vaccination. The previous experience with Rotavirus Vaccine, 

Live, Oral, Tetravalent (RotaShield®) identified these as possible risk windows and because 

of biological plausibility. As of February 14th, 2007, VAERS had received 35 confirmed 

reports of intussusception; 50 percent, or 17, of these reports were within 1 to 21 days after 

RotaTeq administration and of these 17 reports, 11 were within one to seven days of RotaTeq 

vaccination. Categorizing the VAERS intussusception reports by age of onset, it was found 

that within 1 to 21 days of vaccination, seven cases were in the first group, 6 to 14 weeks; 

nine cases were in the second group; and one case was in the third group. In the second age 

window of one to seven days after vaccination, five cases were in the first age group, 6 to 14 

weeks; six were in the second group; and none were in the last group. 

These data were used to assess the observed versus expected calculations for the first time 

window of interest, which is the 1-to-21-day time period after vaccination. VAERS has 

received 17 reports within 1 to 21 days of vaccination, whereas one would expect 

approximately 52 cases of intussusception to occur by chance alone within this time period, 

after adjusting for age. For these expected calculations, the manufacturer's distribution data 

were used, and VSD was used for the background incidence of intussusception and the age at 

vaccine administration. The data indicate that the number of observed cases does not exceed 

the expected number within the 1-to-21-day window, and the reporting rate is 0.32. In 

addition, the observed number of cases does not exceed the expected within each of the three 

age strata. 

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18

Within the one-to-seven-day window, VAERS has received 11 cases of confirmed 

intussusception. Approximately 17 cases would be expected to occur by chance alone after 

adjusting for age. Again, the observed number of cases does not exceed what one would 

expect to occur by chance. Although the numbers are small for each of the three age strata, 

the observed numbers are also within the expected for the three age strata.

Several assumptions should be kept in mind when interpreting the data. First, baseline 

intussusception rates can vary depending on the source of the data. The VSD data may not be 

nationally representative, but they are very robust for that HMO population. The 

completeness and accuracy of the ICD-9 code for intussusception are not well known. For 

example, some evidence suggests that databases may actually underestimate the true 

background rate. Intussusception cases may be discharged from the emergency department or 

short-stay setting, and they would be missed if one just used inpatient databases. In fact, one 

study suggests that approximately 40 percent of intussusception cases may be managed in the 

ED or short-stay setting, making the expected number of cases actually higher. 

Another assumption regards the reporting completeness of intussusception to VAERS. 

Indirect evidence suggests that the reporting of intussusception is common. Since the 

RotaShield experience, awareness of potential intussusception after vaccination has been high 

among healthcare workers. For instance, in the data presented on the current RotaTeq 

vaccine, half of the VAERS intussusception cases were outside the 1-to-21-day window and 

many of these cases were as far as 45 to 60 days after vaccination. 

The third assumption involves the number of doses administered. Although there is 

distribution data from the manufacturer, it is unclear whether there is substantial lag time 

between the distribution and administration of vaccine doses. Past experience suggests that 

the delays tend to diminish as vaccine coverage rises. Background IS rates vary depending on 

the age at which the children receive the vaccine. VSD data was used to determine the age of 

vaccination for the expected rate calculations and compared with data from U.S. 

immunization registries, they appear to be similar. 

In summary, the observed reporting rates of intussusception did not appear to be greater than 

rates expected to occur by chance alone. Nonetheless, these data are dynamic and need to be 

interpreted with limitations. The CDC continues to support the ACIP recommendations for 

routine immunization of all U.S. infants with three doses of RotaTeq at two, four, and six 

months. Ongoing monitoring and refinement will be critical, and plans are in place to provide 

healthcare providers and public health authorities with current updates. 

 

Discussion

Dr. Abramson asked what the confidence interval was for the reporting rate around that first 

week. If there was absolutely no association, one would think it would be fairly even out 

across the days. Dr. Melinda Wharton responded that the data in question was from the casecontrol study where there was active case finding in hospitals, and there is near certainty that 

all of the cases were found. However, cases soon after vaccination are more likely to be 

reported and it is actually quite remarkable that so many late cases were reported. It does 

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19

appear that there is clustering the first week, but the comparison to that isn't with how many 

cases are at later intervals but how many cases are expected in that first week. If there were 

unbiased ascertainment, where cases that occurred later are actually known as opposed to 

relying on people to report them, the graph would probably look very different. 

 

Dr. Ban Allos wondered how the message in the media became so distorted and what could be 

done to make sure that doesn't happen again. Dr. Patel noted that the media headline was 

different from the body of what was presented in most of those articles. 

 

Dr. Janet Gilsdorf asked if the criteria for hospitalization had been standardized. Dr Payne 

replied that there was a series of inclusion and exclusionary criteria, which were implemented 

to standardize criteria across the three sites. 

 

Dr. Baker asked whether each of the three sites was tested according to some standardized 

protocol. Dr. Payne replied that all AGE cases were enrolled in the study according the 

inclusion and exclusionary criteria. However, in normal practice the EIAs are differentially 

applied. There was standardization for differential specimen collection and differential 

enrollment. Sometimes specimens weren't able to be collected from all the other patients due 

to a number of factors. Dr. Baker then asked whether, in terms of ongoing disease-burden 

estimates, these sites had registries or a mechanism for seeing unvaccinated, partially 

vaccinated children and rates of disease. Dr. Payne replied that starting this year, detailed 

information was being collected on vaccination status of all the cases and exactly how many 

doses of how many vaccines study enrollees had received. 

 

Ms. Stinchfield asked about data on use of the vaccine in special populations, such as 

premature infants in neonatal intensive care units, with or without GI problems; or perinatally 

exposed HIV infants; and if there was any guidance for clinicians. Dr. Payne replied that the 

sample size was very small from the first year, so it has not yet been possible to stratify 

beyond general age ranges and some calendar splits. 

Dr. Jane Seward, NCIRD, referring to the apparent clustering in the first seven days, noted 

that the majority of those cases were reported early in October, and at the time some 

wondered if they may have represented an unrecognized adenovirus outbreak. The fact that 

they haven't continued to be reported in clusters as the months progress is reassuring. 

 

Dr. Stan Grogg commented that by the expected versus the number of cases, it might appear 

that the vaccine is protective against intussusception, and that's not what the media have said. 

Dr. Patel responded that the rate ratio of 0.32 does certainly imply that, however it likely 

reflects underreporting within that time window of 1 to 21 days. As the 1-to-7-day window 

closes, the rate ratio goes up and reporting is more complete. 

Dr. Sam Katz, IDSA, asked how many of the reported intussusceptions were corrected or 

remedied radiologically, in contrast to those that went to surgery. Dr. Patel replied that of the 

35 cases, 13 were reduced by barium enema, 8 required surgical resection, 12 required 

surgical reduction, 2 reduced spontaneously, and 2 were still undergoing investigation. 

 

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Dr. Parashar cautioned that one should be careful not to interpret those rates to be protective, 

even though statistically significant for 1 to 21 days. There are too many assumptions in the 

data, such as reporting completeness and doses distributed versus doses administered, etc. At 

this point, the only take from the data is that it's not higher than what would be expected. 

 

Dr. Plotkin shared a headline from the Bucks County local newspaper: "New childhood 

vaccine put on hold. The government says it's unknown whether the recently approved 

RotaTeq is responsible for a potentially life-threatening bowel obstruction." He said it was 

not surprising that the press got it wrong because reading the FDA statement without any 

prior knowledge creates a number of doubts. The question of how to communicate safety 

questions applies to all vaccines. Organizations could avail themselves of expertise in 

communication issues and the CDC and FDA should synchronize their statements when 

important issues come up. Since RotaShield was taken off the market for a safety issue, an 

estimated 400,000 American children have been hospitalized because of rotavirus, which 

might have been prevented by a vaccine. Two companies went to a great deal of expense to 

develop a safer vaccine. If there is a small excess risk, one would hope that the impact of the 

announcement would be much smaller than those cases not prevented by rotavirus vaccine 

during the interval. Dr. Schuchat added that communication needs to be speedy, nimble and 

flexible and that there was good communication between FDA and CDC. However, those 

agencies do not control the media and the headline writers are not the same people who write 

the articles. 

Dr. Paul Offit, Children's Hospital, Philadelphia, referred to the report that over 28,000 

children now have been inoculated with RotaTeq through the VSD. Looking back on the 

RotaShield experience, he asked if there was there a number administered to the VSD that 

signaled there may have been a problem. Dr. Haber recalled that there was no rapid cycle at 

that time, but it could be shown retrospectively, if the rapid cycle was used after a few weeks. 

Dr. Parashar cautioned that though it is reassuring that there were 28,000 doses given with no 

cases reported, in that age group less than half a case would be expected. Going back to 

RotaShield, with a 30-fold risk two weeks after vaccination, it could have been picked up 

sooner, but if the risk elevation is substantially smaller, power to do more at this state is very 

limited.

Dr. Davis said he thought that if the relative risk with this current vaccine were as high as was 

seen with RotaShield, then it would be appearing now. The new vaccine has exceeded the 

number of doses administered by which an elevated relative risk was detected with 

RotaShield. In essence, the time period during which this would have been picked up had the 

relative risk been 25 or 30 has already been exceeded. 

 

Dr. Georges Peter, Brown Medical School, noted that considerable efforts had been made 

over the years to educate medical writers with varying success, but headline writers had not 

been targeted to the same extent. Often the public just reads the headline and not the story. 

He then asked whether there were any data available from registries on whether or not 

pediatricians and family physicians are actually following the guidelines, in terms of 

administration of the first dose at 6 to 12 weeks and the second dose at the appropriate 

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21

interval. Some preliminary data indicate that a significant portion of doses may be given at an 

older age, which is not desirable. Dr. Parashar referred to the slide with the VSD dose 

distribution by age to answer the second question. Dr. Schuchat responded to the comment 

about headline writers pointing out that inflammatory headlines help solicit reports. 

 

Dr. Abramson closed this session by saying he sensed the ACIP was happy going forward on 

this issue. 

 

THIMEROSAL: REVIEWING THE EVIDENCE

Dr. Jay Liebermann, Pediatric Infectious Disease Specialist, University of California, 

Irvine 

Dr, Abramson introduced this session by saying that since ACIP members rotate and it has 

been awhile since the evidence around thimerosal and its potential side effects has been 

discussed, ACIP members had asked for a review. 

 

Dr. Liebermann explained that preservatives are required by the FDA for use in multi-dose 

vaccines, except for certain live viral vaccines, due to episodes of bacterial contamination of 

biological products that occurred early in the twentieth century; for example, Staphylococcus 

aureus contamination that led to local infections, systemic infections, and even deaths. 

Thimerosal is an organic mercury-containing preservative that has been used in more than 30 

U.S. licensed vaccine since the 1930s. The primary purpose is to prevent microbial growth 

during storage and use. It is also used in the manufacturing process for some vaccines, for 

example, to inactivate vaccine antigens in the whole-cell pertussis vaccine. 

There are three forms of mercury. One form is an organic mercury, of which the two primary 

forms and ethyl and methylmercury. Ethylmercury is the form used in some vaccines. 

Mercuric salts are found in batteries and elemental mercury, e.g., quicksilver. Mercury is 

ubiquitous in the global environment; 95 percent of environmental mercury resides in soil and 

is released into the environment by burning fossil fuels such as coal and petroleum. It can 

also be released from rock erosion and volcanoes. It has been estimated that increases in 

power-plant emissions and industrial uses over the past century have tripled the amount of 

environmentally available mercury. Atmospheric mercury can be deposited on the surface of 

bodies of water, where elemental mercury is converted to methylmercury, usually by bacteria, 

and ingested by fish. The principal source of human exposure for organic mercury is fish 

consumption, particularly fish higher in the food chain. For an example, a can of tuna 

contains about 28 micrograms of methylmercury. Mercury can also be found in breast milk if 

the mother has concentrations in her system and in some cosmetics used by certain ethnic 

groups, as well as some herbal remedies and dental amalgams. 

Mercury is a known neurotoxin, and the fetal brain appears to be especially susceptible to 

exposure to organic mercury. There have been outbreaks described with high-dose exposures. 

One was in Japan in an area called Minimata, where industrial pollution heavily contaminated 

the ocean waters with mercury. When locals ate contaminated fish, it caused many cases of 

mercury poisoning, deaths and infants born with severe developmental disabilities, including 

cerebral palsy, mental retardation, and seizures. In Iraq, there was an incident of grain 

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22

contamination in the early seventies, causing many cases of mercury poisoning and deaths, 

and infants were also born during that time with severe developmental disabilities. In this 

case, researchers were able to document to some degree a dose-related response, higher levels 

being associated with more severe disability. 

In the 1980s, two large cohort studies tried to correlate prenatal methylmercury exposures 

with neurodevelopmental outcomes. One study in the Faroe Islands was able to show an 

association between mercury levels in the mother's hair and cord blood and 

neurodevelopmental outcomes at seven years of age. This study is extremely important 

because the data were used to try to determine a level of mercury exposure to the fetus at 

which or below which one would not see effects on neurodevelopmental outcome. These 

were used to develop federal guidelines for safe levels of mercury exposure. A similar study 

was done in the Seychelles and no association was found, although the exposure to mercury 

was about the same. The reason for the difference is not clear. In the Seychelles, exposure is 

through fish, which they eat often. In the Faroe Islands, most of the mercury exposure comes 

from eating pilot whales, which are contaminated with other things such as PCBs. The role 

PCBs might be playing in the neurodevelopmental outcomes is not clear. 

Thimerosal is about 50 percent ethylmercury, whereas methylmercury is the predominant 

form of organic mercury in the environment. Many childhood vaccines contain between 12.5 

to 25 micrograms of mercury. Through the eighties, it was in flu vaccine and various 

diphtheria/tetanus/pertussis vaccines. In the late eighties and early nineties, as hepatitis B and 

Hib vaccines were added to the immunization schedule, there were now more vaccines in the 

childhood immunization schedule that contained thimerosal. 

A goal of the 1997 FDA Modernization Act was to compile a list of drugs and foods that 

contained intentionally introduced mercury compounds and provide a quantitative analysis. 

The FDA concluded that infants who received thimerosal-containing vaccines at several visits 

could exceed the total mercury exposure recommended by Environmental Protection Agency 

guidelines. These guidelines for exposure were set to avoid toxicity to the fetus. They were 

based on studies of oral ingestion of methylmercury, usually through fish. It was assumed 

that, since digestion was going on daily over months, the half-life of methylmercury was 

about 50 days. The aim was to develop a no-effect level that would be safe and then put in a 

safety factor. For the EPA, that factor was about tenfold and they set the level at 0.1 

micrograms per kilogram per day of methylmercury. FDA guidelines were a little higher 

because of how they analyzed the data and their safety factor, but these are not toxic levels, 

they are safe levels, set to minimize the chance of neurodevelopmental problems. Looking at 

different ages, specifically females in the first six months of life by different weights and 

different body percentiles, and calculating by the different standards for mercury (EPA, FDA, 

WHO, etc.), one can ask what an acceptable or safe level of mercury would be for that daily 

exposure. 

These exposure limits had a number of assumptions. For vaccines, there’s an assumption that 

the toxicity and pharmacokinetics of ethylmercury in thimerosal and methylmercury are the 

same, but exactly how they relate is unknown. There's some evidence that ethylmercury is 

excreted faster in the stools, and some evidence in monkeys that less goes to the brain. They 

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23

also assume that the effects of low-dose oral exposure daily are the same as a bolus IM 

injection and that the susceptibility of the infant to toxicity is the same as that of the fetus. 

There are also many assumptions when making the leap from what is happening to a 

developing fetus to giving an injection at two and six months of age. However the conclusion 

was that children receiving all possible thimerosal-containing vaccines could receive quite a 

bit of thimerosal compared to the EPA guidelines - 200 micrograms by six months of age. 

For girls, the recommended upper limit was between 65 and 106 micrograms depending on 

weight, and by two years, 275 micrograms. 

In 1999, a joint statement by the AAP/FDA U.S. Public Health Service urged manufacturers 

to remove thimerosal from vaccines as soon as possible, as a precautionary measure to 

maintain the public's trust in immunization. There was no evidence at the time of any harm 

caused by the low levels in vaccines. The big uproar came from pediatricians who saw their 

immunization schedule potentially disrupted. 

Thimerosal as a preservative was removed from most childhood vaccines by 2001 and the last 

lots of thimerosal preservative-containing vaccines expired in January 2003. It is still being 

discussed only because of ongoing litigation in both state courts and the Vaccine Injury 

Compensation Program. Thimerosal is still contained in some of the flu vaccines routinely 

given to children since 2004. There are also vaccines that contain trace, often unmeasurable, 

levels of thimerosal. 

During the nineties, the number of persons reported to be receiving services for autistic 

spectrum disorders increased substantially. Rates are tenfold higher than in the 1970s; in the 

MMWR, rates ranged from 4.5 to almost 10 per thousand eight-year-olds. Newspapers have 

reported that one in 150 children has autism. A study published in Nature Genetics from the 

Autism Genome Project analyzed genes from more than 1100 families with at least two 

children with autism. There is some very promising research identifying some loci of genes 

on chromosomes, particularly Chromosome 11. 

While researchers are getting closer to understanding where autism comes from, especially 

regarding the strong genetic component, they still do not know if an environmental hit is also 

necessary. There’s some evidence that it occurs in a susceptible host in whom something else 

happens. Prenatal exposures, such as Thalidomide, have been linked with autism. 

Interestingly, those children who developed autism had very specific birth defects, which 

suggested a specific time of onset. Congenital rubella, as well, had been associated with 

autism. To date, there's no good evidence that postnatal exposure to anything is linked with 

the onset of autism, but the concern about mercury in thimerosal in the vaccines remains. A 

paper published in Pediatrics several years ago looked at autism and some of the neurologic 

characteristics, comparing it to the known neurotoxicity of mercury. In comparing the two, 

they were dissimilar. 

The Institute of Medicine was commissioned by the CDC and the NIH to review specific 

vaccine-safety topics, including vaccines and autism. In their 2001 report, they concluded that 

the evidence was inadequate to accept or reject a causal relationship between exposure to 

thimerosal from vaccines and autism, ADHD, speech and language delay. The reason was 

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24

that there were no published epidemiologic studies examining the potential relationship 

between thimerosal exposure and neuro-developmental disorders. They did conclude, 

however, that because mercury is a known neurotoxin and because prenatal exposures to 

methylmercury have been documented to negatively affect early childhood development, a 

potential biological mechanism could at least be hypothesized and was worth investigating. 

To test this hypothesis, ideally there would be a double-blind, randomized, placebo-controlled 

trial, randomizing children to get thimerosal-containing vaccines or not and following them 

for many years. However the sample size would be prohibitive and it couldn’t be done from 

an ethical standpoint either, since the goal was already to remove thimerosal from vaccines. 

This leaves retrospective cohort studies, looking at a well-defined cohort, their exposures to 

thimerosal and gradations of exposure, and neuro-developmental outcomes. In addition, 

ecological studies can track changes in incidence of autism and other neuro-developmental 

disorders as the use of thimerosal changes. 

The first published study, from Denmark, was a population-based cohort study of all children 

born in that country between January 1990 and December 1996, a total of almost half a 

million. Their health care system was able to track and compare children vaccinated with 

thimerosal-containing vaccines with children vaccinated with thimerosal-free vaccines, in 

general, the diphtheria/tetanus/pertussis vaccines as they evolved. The use of thimerosal was 

discontinued in 1992. They were able to identify 440 cases of autism and 787 with other 

autistic spectrum disorders. They found that the risk of autism and autistic spectrum disorders 

did not differ significantly between groups. For example, for autism, the risk ratio was 0.85, 

showing no link between getting vaccines containing thimerosal and the development of 

autism and autistic spectrum disorders. In addition, they found no evidence for a doseresponse association. 

The next big study was done in the U.S., using the Vaccine Safety Datalink project, which 

was developed as a screening study and initiated in late 1999. The study was devised to 

examine the association between thimerosal exposure from childhood vaccines by one, three, 

and seven months of age and various diagnoses, including autism, speech and language 

delays, tics, and ADD. This study was in two phases; the first phase at two managed-care 

organizations (HMOs A and B) looking at all children born between January 1992 and 

December 1998. The second phase was done at a third managed-care organization (HMO C). 

The preliminary findings showed a statistically significant dose-response association between 

exposure to thimerosal at three months of age and any of various neuro-developmental 

disorders. 

These findings were discussed at a meeting in Georgia, in early June 2000. Several 

consultants were invited to review the findings and advise the CDC. They were ultimately 

presented at the June ACIP and then at the Institute of Medicine. The meeting was the focus 

of the articles in Rolling Stone and Salon, which suggested that something nefarious was 

going on because the final published report findings were different from the preliminary 

findings. They differed because after peer review the authors corrected errors and refined 

their analytic methods, adjusting for utilization of healthcare services. The major influence on 

when children got the vaccine was how often they went to the doctor, which would also 

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25

influence diagnoses and behaviors. They also extended the follow-up period, so they had 

more diagnoses. But the fact that the final results differed from the preliminary just fueled 

suspicions that something was being hidden. 

In the published paper, in Phase I, the cumulative thimerosal exposure at three months was 

associated with tics. At HMO B, the cumulative exposure at three and seven months was 

associated with language delays, with relatively low relative risks. In Phase II at HMO C, 

there were no significant associations between cumulative thimerosal exposure at one, three, 

or seven months and speech or language delay, ADD, or tics. Only HMO B had a sufficient 

number of cases of autism to perform an analysis, and even in the preliminary analysis, autism 

was not significantly associated with thimerosal exposure. The conclusion was that there was 

no evidence of a clear association between thimerosal exposure in infant vaccines and specific 

neuro-developmental disorders. But results among the HMOs were inconsistent, and so 

further investigation was recommended. 

The next study was a retrospective cohort study looking at over 100,000 children born in the 

U.K. between 1988 and 1997, which evaluated the relationship between exposure to 

thimerosal via DT or DTP vaccines and neuro-developmental outcomes. There was some 

evidence for higher risk of tics with increasing doses at four months, but no negative 

associations were found between thimerosal exposure and ADD, general developmental 

disorders, and unspecified developmental delay. 

A problem with these cohort studies is that diagnostic accuracy of outcomes such as ADD or 

autism is not perfect. For example, in the study just presented, 90 percent of the tics were 

transient. The doses of thimerosal also differ among the studies. Cohort studies are best used 

to quantify a risk to exposure rather than to prove its absence. 

Dr. Liebermann then talked about ecological studies. In 2000 the Institute of Medicine 

presented data showing the amount of thimerosal in vaccines and cases of autism diagnosed in 

California by year of birth. The data show increases in the amount of thimerosal given to 

children by birth cohort and increases in the rates of diagnosis of autism, and they track fairly 

well. The rate of autism rose in the mid-eighties, even before an increase in thimerosal. 

However, anything that increased in the nineties tracks with diagnoses of autism, including 

use of home personal computers and cell phones. This kind of data only shows that two 

things were increasing at the same time. It says nothing about a possible association. 

An ecological study in Denmark analyzed data from almost 1,000 children diagnosed with 

autism over 30 years. Thimerosal was used in childhood vaccines from the early fifties until 

1992, and there was no trend for an increase in autism up through 1990. From 1991 to 2000, 

the incidence of autism increased, after thimerosal was discontinued from vaccines, 

suggesting no relationship between thimerosal and autism in Denmark. 

In Sweden, a similar ecological study analyzed inpatients diagnosed between two and ten 

years of age with autism over a 12-year period. It looked at the average cumulative dose of 

thimerosal using vaccine-coverage levels. Thimerosal was eliminated by 1993, after which 

the data show no decline in autism, in fact, it continued to rise. From 1980 to 1996 there was 

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26

almost a doubling in cases. Looking at all these studies, the Institute of Medicine report in 

2004 said the evidence favors rejection of a causal relationship between thimerosal-containing 

vaccines and autism. 

There have been studies showing an association: two ecological studies and three studies 

using passive reporting data, all by the same authors, who are the only ones who ever found a 

relationship between MMR vaccine and autism. Quoting the Institute of Medicine, "These 

studies cited have serious methodological flaws. Their analytic methods were nontransparent, 

making the results uninterpretable and therefore noncontributory with respect to causality." 

They used the VAERS database to calculate an incidence of neurodevelopmental disorders 

and heart disease following thimerosal-containing versus thimerosal-free DTaP vaccines. It 

might be possible with rare events, like intussusception or Guillain Barre, but not autism. 

They found an exponential distribution link between autism, speech disorders and heart arrest, 

and thimerosal dose. VAERS has many limitations. It's passive and there's underreporting, 

incomplete reporting, and, certainly, bias. It can't be used to calculate incidence and the cases 

weren't verified. These authors also did an ecological study with U.S. Department of 

Education data. They compared autism to thimerosal exposure by birth cohort and showed a 

linear relationship - as thimerosal in vaccines increased, autism increased. However, that 

does not prove causality and how they actually got their numbers is not clear. 

A paper published by Sarah Parker and colleagues carefully analyzed the studies looking at 

autism and thimerosal exposure, emphasizing the quality of the studies. How good are the 

data? Are exclusion criteria defined and outcome measures precisely described? Is there a 

basis for the sample size? Is bias controlled? The paper concluded that while the studies that 

do not support a relationship are not perfect, one can understand the methodology. The 

studies that do support a relationship are worthless to evaluate any possible association 

between thimerosal and neurodevelopmental disorders. 

Since the IOM report, there have been two new studies. In the U.K. a longitudinal study of 

more than 14,000 children determined the ages at which they got thimerosal-containing 

vaccines, calculated levels of mercury exposure, and compared them with development at 

between 6 and 91 months of age. Again, the results showed no evidence of any harmful effect 

of early exposure to thimerosal on neurological or psychosocial outcomes. Indeed, the 

unadjusted results suggested a beneficial effect of thimerosal exposure. For example, those 

who had thimerosal had less hyperactivity and better model development. When results were 

adjusted for possible confounders, eight of the nine significant associations actually showed a 

beneficial effect, not suggesting that thimerosal is protective, but no evidence of harm. The 

only negative association was poor pro-social behavior at 47 months. 

The last study, published this past year from Montréal, looked at almost 30,000 children and 

evaluated the relationship between the development of pervasive developmental disorder and 

changes in vaccines, thimerosal exposure as well as MMR. The cumulative exposure to 

thimerosal increased and decreased over time. By 1996, it was out of the vaccines. There 

were a total of 182 children with pervasive developmental disorders. Looking at average 

thimerosal in the vaccines and diagnoses of autism by birth cohort, the same trend of 

increases in cases over time can be seen, even in those infants who were not exposed to 

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thimerosal. This seems to be the most compelling evidence of no association. If thimerosal is 

responsible for autism, as it is removed from vaccines, cases of autism should decline, but that 

is not happening. 

Data from California from 2002 to 2006, which has been submitted for publication, indicates 

that cases of autism in three- to five-year-olds and six- to nine-year-olds have continued to 

increase. There's absolutely no evidence of any decrease in cases of autism since thimerosal 

has been taken out of vaccines. Instead, cases have continued to climb. The science shows 

that in well-designed epidemiologic studies, there's no association between thimerosal 

exposure from vaccines and autism. The ecological studies show that autism does not go 

down when thimerosal is removed from childhood vaccines. Studies in tissue cultures and 

animals provide interesting information about toxicity, but they do not translate to what is

going on in children. 

Finally, Dr. Liebermann talked about unintended consequences. For example, the birth dose 

of hepatitis B vaccine is universally recommended to prevent against failures of screening, but 

hospitals discontinued the routine birth dose in 1999, after the joint statement until 

thimerosal-free vaccines became available. However, by 2006, vaccine-coverage rates for the 

birth dose were still below the 1999 levels. As a consequence, hundreds of children in the 

U.S.were born to hepatitis B-positive mothers and, for various reasons, not screened. The 

infants did not get their dose of hepatitis B vaccine and, therefore, were at risk of becoming 

chronic carriers of hepatitis B. Concerns about vaccine safety and the fear that the MMR 

vaccine caused autism caused MMR vaccination rates to fall in the U.K. with subsequent 

outbreaks of these vaccine-preventable diseases. Fear of thimerosal caused some high-risk 

children to avoid the recommended flu vaccine. So there are real consequences to every 

decision made.

California has passed legislation banning thimerosal-containing vaccines for children under 

three years and pregnant women in that state. A provision was put in for an exemption in case 

of emergency or vaccine shortage. In fall 2006, there was a delay in shipping some doses of 

flu vaccine for children three years of age and younger because one virus in the vaccine was 

slow growing. A group of medical organizations requested an exemption, which was granted. 

There are no data to show how this influenced flu vaccines in California, but flu vaccines are 

time-dependent and not having vaccine makes it very hard to vaccinate children. Anything 

that limits the availability of vaccines for children potentially puts them at risk.

 

In conclusion, the evidence does not support an association between thimerosal and autism. 

The consistency among these well-designed studies lends strength to their individual 

conclusions. Autism is increasing and research should be directed towards areas of more 

promise. 

 

Discussion

Dr. Harry Hull asked if there were any other possible reasons why the diagnosis of autism 

might be increasing. For example, there was something in the popular press recently saying 

that autism is going up but mental retardation is going down because it's being reclassified, or 

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28

that support programs for families with an autistic child might be reaching more children who 

are diagnosed with autism. Dr. Liebermann replied that part of the increase is related to 

changes in diagnostic criteria and accessibility to services. But among pediatricians, there's 

also a sense of a true increase, which is why it’s important to investigate what is leading to 

that increase. 

 

Dr. David Salisbury noted that the levels reported in the U.K. schedule were lower than those 

experienced in the U.S. However, the vaccines were given at two, three, and four months in 

the U.K. rather than two, four, six, in part because children are actively called in through 

registers. The fact that the U.K. studies showed no association is important because the ages 

map across quite reasonably and compliance with the recommended ages for vaccination is 

very tight. 

VACCINE SUPPLY

Dr. Greg Wallace, MD, CDC/NCIRD 

Dr. Wallace addressed three topics related to vaccine supply: influenza vaccine distribution; 

implementation of new vaccines and specifically how the process works; and a brief update 

on varicella zoster-based vaccines. 

Influenza Vaccine Distribution

In the eighties, about 20 million doses of influenza vaccine were made annually, nearly all 

distributed each year, but by today's standards, there was relatively low use. Into the nineties, 

the amount of vaccine produced increased from about 30 million doses to over 85 million, but 

there was greater variability in the amount of vaccine produced and not distributed. This year, 

over 110 million doses were produced and more than 100 million have been distributed. 

Recent history shows both problems and improvement over the last several years. In 1999, 

vaccine was distributed on time and most of what was produced was distributed. In 2000 and 

2001, there were delays, which led to considerable scrambling to produce late-season vaccine. 

By then, demand was down and even though there were many complaints about not being 

able to get vaccine, much of the vaccine produced wasn't distributed. In 2002, a record 

number of doses was produced (95 million), but it exceeded demand, so a significant amount 

remained undistributed. The following year, production was closer to expected demand: 80 to 

85 million doses. That vaccine was mostly distributed, but there was a report of pediatric 

deaths in November, causing many requests for new vaccine. Most of the late season 

production was never distributed because demand waned rapidly. 

There was a real shortage in 2004 when a manufacturer dropped out late. In 2005, capacity for 

the manufacturer who dropped out was mostly restored, but production was delayed. This 

year, early projections were for over 100 million doses and even more if an additional vaccine 

was licensed. Since early December 2006, over 102 million doses have been distributed, 

almost 20 million more than have ever before, but there continue to be concerns over timing, 

equity, and supply-demand mismatches. 

 

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A cumulative distribution curve shows the variability that occurs in October. In 2006, 2005 

and 2004, the shortage year, while distribution is modest, it continues into January. 

The same data on a monthly cumulative curve show the vaccine mostly coming out in 

September with production over by October. However, the peak of distribution is usually in 

October, which can be awkward for planning because a week or two of delay can make a big 

difference. 

One of the big concerns is about equitable distribution, both regionally and by provider type. 

Most years, there are reports that a state doesn't have any vaccine. This year there is a secured 

data network that manufacturers and major distributors provide data to voluntarily, which 

makes it possible to evaluate how vaccine is distributed by HHS region. The data on the 

distribution rate over time, or the number of doses per thousand, indicate very tight agreement 

among regions, so everybody is basically getting the same amount of vaccine no matter what 

the time period. 

The other common concern is distribution by provider type. Data on distribution by provider 

type show that no matter what the time period, private providers receive 40 percent or more of 

the vaccine distributed. Vaccine does not get distributed to providers last. There is also 

survey data suggesting that around 40 percent of the public seek their flu vaccine from their 

private provider. For distributors, there is an initial increase in September, but it flattens out 

quickly. For state and local health departments, the federal government and the military, 

equilibrium is not reached until well past the November time period. Even though they're a 

relatively smaller part of the influenza vaccinators, there's clearly room for improvement here 

as far as equitable distribution over time. 

In summary, there have been overall improvements in distribution. It's a very complex and 

dynamic system with multiple variables and some improvement is still needed in the publicsector distribution. 

Implementation of New Vaccines [Routine Pediatric Vaccines since 2000]

Dr. Wallace described the process for the implementation of new vaccines. After FDA 

licenses the vaccine, ACIP votes to approve it, and a vote for a VFC resolution follows. Next 

CDC secures a vaccine contract and grantees can purchase vaccine through those contracts. 

They can use three different funding sources: the VFC funding, 317 grant funding, and state 

and grantee funding. Sixty-three grantees purchase vaccine directly through CDC contracts; 

60 of those 63 grantees are VFC eligible (three Pacific islands are not VFC grantees). 

Dr. Wallace then showed a table of new vaccines implemented since 2000, including dates of 

FDA approval; the ACIP approval, which would be the same day that the VFC resolution was 

approved; date of the CDC contract; and when the MMWR was published. A relatively rapid, 

stepwise process can be seen, which occurs with the most variability around the timing of the 

MMWR presentation. 

For pneumococcal conjugate vaccine and the number of grantees who are using VFC funding, 

317 funding, and state and grantee funding, there is a leveling out after six or seven months. 

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There's a gap between the number of grantees using 317 funding and VFC funding and 

another gap between state and 317 funding. But since its inception to the present, eventually 

almost everybody was using 317 funding as well. 

 

In contrast, there was a very tight progression from FDA licensure to MMWR publication for 

MCV4. For this vaccine, CDC contracts represent currently about 45 percent of the market. 

There are a few reasons for the relatively slower uptake and CDC being a smaller percent of 

the market. People were aware of the relative shortage or demand-production mismatch, so 

CDC contracts were prioritized based on the VFC population. As that supply eases, this may 

change. Initially more vaccine uptake was occurring in college freshmen, which would 

account for CDC being a smaller percentage. As it becomes more of a routine 11- to 12-yearold vaccine, a change will be seen. 

TDaP, also an adolescent vaccine, was ready to come out of the chute right away. Public 

health was more excited about the TDaP because of the pertussis-outbreak responses needed. 

Here 317 comes up pretty quickly and there is always a gap between state and 317 funding. A 

common complaint is that a new vaccine cannot be implemented until the MMWR is 

published, but that clearly wasn't the case for this vaccine. For TDaP, CDC is about 50 

percent of the market. 

For rotavirus vaccine, the same pattern of a quick uptake and an early gap between funding 

sources is seen. Right now, CDC is about 65 percent of the market, which has been common 

in the past, where the VFC program leads implementation, particularly for an infant vaccine. 

For HPV vaccine there are data for only six months, but utilization of VFC has been on a 

rapid uptake. It's too early to know what will happen with 317, but CDC contracts already 

account for about half of the market. 

In summary, VFC funding leads implementation of new vaccines. The extent and timing of 

the 317 and grantee funding gap vary varies considerably by vaccine and over time, without 

addressing the question of whether or not there's enough 317 vaccine to implement some of 

these programs. The time lines for implementation are relatively efficient, although the 

funding for 317 and state funding may not be adequate. In conclusion, the state funding for 

any of the vaccines never exceeds half of the grantees, so there's certainly a gap there. 

Update on the Varicella-based Vaccine Supply 

Varicella-zoster virus bulk is used to manufacture the varicella, MMRV, and zoster vaccines. 

Merck recently announced that they are having lower than expected yields in their bulk 

product and have ceased producing the bulk while they work on addressing the yield issues. 

They currently have a fair amount of bulk available and expect to have an adequate supply for 

all the vaccines, although MMRV supply may be limited in the future and may run low late in 

this calendar year. 

As has been done for other vaccine-supply issues recently, CDC convened an ad-hoc supply 

group that includes ACIP, CDC, FDA, and other stakeholders to meet with the manufacturer 

regularly and will follow this issue closely. In the MMWR coming out on Friday [February 

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31

23, 2007], the main message is that there will be no changes in the recommendation even if 

MMRV becomes in short supply late in the year. CDC projects there will be adequate 

varicella and MMR supply, and the two would be equivalent to administering one MMRV 

dose. Vaccine supply will continue to be monitored by the stakeholder work group and at any 

time, if MMRV is not available, varicella vaccine and MMR are equivalent. Updates will be 

provided as necessary. 

 

Discussion

Dr. Julie Morita mentioned that the influenza vaccine distribution data were extremely helpful

for showing that private providers were actually getting the bulk of vaccine and in addressing 

issues raised by the press. 

 

Dr. Ciro Sumaya asked whether there really were breakups or delineations in aggregate data 

within states and what was the lowest level of useful data on distribution and supply. The 

basis for the question was to get a better sense of any variability occurring at lower levels that 

isn't picked up at the national and public-health levels. Dr. Wallace replied that he did not go 

beyond the HHS level, not only because there were a lot of data to evaluate, but breaking it 

down by state and by provider would be a much bigger process. The data do provide good 

information about the equity issues, in that there are some areas for concern that need 

approval. This information has been useful in discussions with manufacturers and 

distributors, but the main point is to allay the overall sense that Wal-Mart gets vaccine before 

everybody else. 

Dr. Sumaya asked how shortages were defined, specifically for influenza. Dr. Wallace said 

he thought a shortage was actually defined by the press or by individuals who had not yet 

received their vaccine. Dr. Baker asked whether distribution referred to when the vaccine is

shipped or when it's received. Dr. Wallace said it was when it was received, but clarified that 

both the manufacturers and the major distributors ship their vaccine within 24 hours of release 

and it gets to at least the next level within 24 to 72 hours, so shipping and receiving are 

essentially the same. If it is going to a middleman rather than to a private provider, that 

information is also captured. 

 

Dr. Tamara Lewis, America's Health Insurance Plans, suggested that the increasing gaps were 

related to the ability to absorb price increases. Without an increase in immunization budgets, 

states are not able to absorb the cost of new vaccines and so some new ones are dropping off 

the state's list. So far, VFC and insurance companies have been able to keep pace, but the 

cost issue around new vaccines is going to become critical and there will be more gaps. Dr. 

Wallace responded that the same could be said for the 317 grantees, who are purchasing more 

different kinds of vaccine but without the same coverage. Dr Abramson commented that 

there would probably be discussion on vaccine financing in June and that the National 

Vaccine Advisory Committee had been given the task of trying to deal with those issues. 

 

Dr. Jon Temte, American Academy of Family Physicians, asked where the mass immunizers 

fit into the distribution by provider type. That's the biggest concern from individual clinicians 

who have the perception that the large-scale retail outlets get vaccine before they do. Dr. 

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32

Wallace was not sure what percentage they represented. He noted that in one region even the 

mass vaccinators go through a middleman, so they do not necessarily get their supply by this 

time in September. 

 

Dr. Georges Peter, Brown Medical School, asked when the herpes zoster vaccine statement 

would be published and whether there were any measures of the uptake of that vaccine. Dr. 

Pickering said the statement was expected to be completed sometime the end of February or 

in March [2007]. Then it will begin the clearance process, so it would be several months 

before it is published in MMWR. Dr. Joan Benson of Merck added that there has been a 

significant interest in Zoster Vaccine, Live (Zostavax®) by healthcare providers. 

Dr. Jeff Duchin from NACCHO acknowledged that, as 317 funds are increasingly used for 

vaccine, it takes away money for infrastructure for vaccine programs at state and local levels. 

He also noted that some states don't distribute vaccine until the official MMWR publication, 

which creates an uncomfortable time period during which the vaccine is available to those 

who can pay cash but not to those who receive it through VFC or 317. Finally he noted that 

the ACIP has recommended HPV for a target group in 11- and 12-year-olds, yet there's a very 

permissive recommendation for VFC women up to 18. He asked how the vaccine would be 

allocated with such a broad cohort. Dr. Wallace responded that the CDC contract was not 

restricting the use of HPV or how much can be ordered based on supply. Dr. Haupt added

that there has been a remarkable uptake of the Human Papillomavirus (Types 6,11,16,18) 

Recombinant Vaccine (Gardasil®) since licensure and there is no supply problem for all the 

cohorts that have been recommended. 

Phil Hosbach, sanofi pasteur, pointed out that publication of recommendations in the MMWR 

also has an impact in terms of when the health plans will actually put it on their formularies 

and allow it to be reimbursable. So while VFC is getting the vaccine, the private side of the 

same office is not getting reimbursed. He also pointed out that the total cost of vaccines 

needed to be put into perspective relative to the total expense of healthcare. Dr. Pickering

noted that provisional ACIP recommendations are placed on the ACIP Web site shortly after 

clearance and there is an attempt to expedite all of the MMWR publications. Dr. Wallace 

added that TDaP may be slightly different than the other vaccines, so even if VFC got here 

right away, it is only about a quarter of the market. 

 

Dr. Baker asked whether health plans recognized what is on the Web in the same way they 

recognize the printed publication. Dr. Lewis said the America's Health Insurance Plans were 

very cognizant of the NIP Web site and used it consistently. Dr. Lett added that in 

Massachusetts they attach the provisional recommendations and send a letter to all the health 

plans as soon as there's a vote and they're available on the Web site, to encourage 

reimbursement. 

Dr. Katz, IDSA, said that a study about funding published by the Institute of Medicine several 

years ago showed enormous variation from state to state. Some states use all their 317 money 

to purchase vaccine, others use it for infrastructure, and then there's a gradation in between. 

Dr. Wallace added that what states report on how they're planning to use the money and how 

they actually spend it can vary as well, even from year to year. Dr. Dean Mason, Wyeth 

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33

Vaccines, stated that the good news was that 32 million dollars have been appropriated for 

317 fund increase this year, the result of an intense lobbying effort by a number of 

immunization coalitions. 

Dr. Katz then asked whether flu vaccine through the CDC contract represented only a small 

proportion of the total flu doses purchased historically. With the recommendations for routine 

immunization of children and the CDC contract becoming even more important to the 

national framework of vaccine purchases, he wondered what the proportion of total purchases 

was for the CDC contract and whether was it increasing. Dr. Wallace replied that the absolute 

number of doses in the contract has been increasing on the magnitude of 1 or 2 million more 

doses a year, but it is still probably less than 10 percent of the aggregate. However, CDC is 

50 percent of the market for sanofi's 0.25 cc vaccine licensed for 6- to 35-month-olds and has 

been consistently since the full recommendation was made. 

Dr. Abramson noted the concern about financing and supply, but reminded the group that 

many others were trying to deal with these issues. 

INFLUENZA

Update: Seasonal Influenza Epidemiology, Virologic Surveillance and Antiviral Drug 

Resistance

Dr. Ban Mishu Allos, ACIP Influenza Workgroup Chair 

Dr. Anthony Fiore, MD, CDC/NCIRD

Dr. Allos opened the Influenza session with a summary of progress in influenza-prevention 

efforts made in recent years. There are now more timely population-based data and more 

effectiveness data based on lab-confirmed infection instead of just URI illness. Critical 

questions being addressed include the need for two doses of influenza vaccine in children, 

which was not understood five years ago. 

Vaccine coverage has improved among infants and toddlers, and rates for the elderly and 

adults are rebounding after the shortage season of 2004/2005. Manufacturing capacity has 

expanded, there is increased availability of preservative-free formulations, and new 

formulations are in the pipeline. There's also improved flexibility for providing vaccine in 

innovative settings, such as schools. However, coverage rates are still too low in many 

groups at high risk for complications. Effectiveness and safety studies are needed yearly, 

especially as recommendations are expanded. Implementation is difficult; flexibility in 

scheduling and capacity are needed and supply delays or shortages continue. Public demand 

is fickle and messages are sometimes confusing in such areas as the optimal time for 

administering influenza vaccine.

 

Dr. Allos reviewed some of the milestones in recommendation changes. In 2000, ACIP voted 

to expand the recommendation for all adults 50 and older, moving closer to what the 

pediatricians have always known, that risk-based recommendations rarely are effective in 

getting the people at risk vaccinated. In 2004, all children between the ages of 6 and 23 

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34

months were recommended for vaccination, as well as women who would be pregnant during 

the influenza season. In 2005, people with respiratory compromise or who have trouble 

handling their secretions were added. Then last year, ACIP voted to include children ages 24 

to 59 months and their household contacts. This was paradigm shift, from vaccinating to 

prevent death or hospitalization to preventing visits to the emergency department and other 

outpatient settings. 

Criteria for expanding vaccination recommendations include safety, effectiveness, morbidity 

and mortality, and hospitalizations. This involves looking at outpatient and emergencydepartment visits, and indirect effects, especially preventing illness among contacts, in 

addition to feasibility, cost effectiveness, and vaccine supply. Regarding expanding the 

recommendations to older children between the ages of 6 and 18, it is important to note that 

children who are household contacts of younger children, people at high risk and the elderly 

are already recommended for annual vaccination. If the recommendation is expanded to

include children ages 5 to 18 years of age, morbidity and mortality would be reduced in the 

children who are themselves vaccinated. Communitywide morbidity and mortality might be 

reduced by indirect effects. However, it may create an expectation of immediate 

implementation of immunization programs for this age group, which could be difficult to 

meet and might exacerbate vaccine supply shortages and distribution delays. Planning for 

recommendation and expansion requires input from many groups: epidemiologists, 

immunologists, vaccine-safety experts, immunization program managers, communications 

experts, manufacturers, economists, education officials, funding entities, and the general 

public. 

A possible time frame for modifying influenza vaccination recommendations is as follows: in 

2007-2008, expand recommendations to include all school-age children 5 to 18 years old, 

address critical issues and develop roll-out plans. A summary of scientific and 

implementation issues surrounding this expanded recommendation could be presented at the 

October 2007 meeting, after which ACIP could assist manufacturers, immunization programs, 

and public-health communication experts in planning for actual implementation in 2008 and 

2009. By 2010, recommendations could be expanded to include household contacts and 

caregivers of school-age children. After the appropriate surveillance studies are done and the 

need is assessed, ACIP might move to a universal vaccination recommendation in 2012. 

 

Dr. Fiore presented the most up-to-date influenza surveillance data, through February 10th. 

First, he showed a map representing current influenza activity across the country, as estimated 

by state epidemiologists. Since October 1, 2006, about 92,000 specimens have been tested for 

influenza viruses; about 9 percent of these were positive. Among the 8300 influenza viruses, 

about 7,000 or 83 percent were Influenza A, and some 1400 were or 17 percent were 

Influenza B viruses. Twenty-eight percent of the A viruses have been sub-typed: 88 percent 

were H1, and 12 percent were H3 viruses. The CDC has characterized 161 of these viruses 

through February 10th. Of the 99 H1N1s characterized, 94 percent were similar to the New 

Caledonia-like virus represented in the vaccine and 6 percent had somewhat reduced titers to 

New Caledonia. In 2007, only seven H3N2 viruses have been characterized so far. Four are 

similar to the Wisconsin-like viruses represented in the vaccine, and three had reduced titers 

to these viruses. 

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35

For Influenza B, 55 viruses were tested. Over the past couple of years both Influenza B 

lineages have been circulating; this year, 67 percent were B/Victoria. Of those, 49 percent 

were similar to the B/Ohio strain, which is represented in the vaccine, and 51 percent had 

somewhat reduced titers. The remaining 33 percent of the viruses were of the Yamagata 

lineage. At this point, 6.7 percent of all deaths are reported as being due to pneumonia or 

influenza; this is measured against a seasonal baseline, but the defined epidemic threshold has 

not yet been exceeded. 

Laboratory-confirmed influenza-associated pediatric hospitalizations are monitored in two 

population-based surveillance networks. The Emerging Infections Program (EIP) data 

indicate hospitalization rates for young children, zero to four years old, and 5- to 17-year-olds, 

for this influenza season and previous seasons. Rates this season are similar to the past couple 

of years, but distinctly below the 2003-2004 season. Data from the New Vaccine Surveillance 

Network has the advantage of going back a couple of more years for comparison, but it also 

just has data for zero- to four-year-olds. 

Surveillance for pediatric deaths began in the 2003-2004 season when it became a reportable 

disease. As of February 15, 2007, CDC has received 15 reports of influenza-associated 

pediatric deaths. Ten children were five years of age or older, three had underlying conditions 

that might have contributed to severity, five had no known underlying conditions, and two, as 

of yet, have unknown previous health status. Four children had MRSA bacteremia and nine 

were unvaccinated. One child was vaccinated. In 2004-2005 and 2005-2006, there were 44 

and 48 deaths respectively, as compared to the first year of reporting, 2003-2004, when 153 

deaths reported. 

Dr. Fiore then talked about antiviral drug resistance during the 2006-2007 year, with reference 

to the emergence of adamantane-resistance Influenza A viruses. Last year was predominantly 

an H3N2 year, and two of eight H1 viruses were adamantane resistant, while 192 of 209, or 

92 percent, of the H3N2 viruses were adamantane resistant. There fewer adamantaneresistant isolates so far in 2006-2007, and relatively fewer H3N2s thus far globally to 

characterize. For H1N1s, 5 of 199, or 3 percent, have been shown to be adamantane resistant, 

compared with 24 of 54, or 44 percent of the H3N2 isolates, which is roughly the same as 

what's being seen among U.S. isolates. Slightly lower proportions are adamantane resistant: 1 

of 91, or 1 percent, for H1N1; and 3 of 10, or 33 percent, for H3N2. In contrast, resistance to 

the neuraminidase inhibitors, oseltamivir and zanamivir, remains rare. A large globalsurveillance network published a paper last year in which, among the many thousands of the 

isolates tested, less than 0.5 percent were resistant to one or the other of the neuraminidase 

inhibitors. So far, none of the 437 isolates tested at CDC has had resistance to these two 

drugs. 

In the October 2006 ACIP meeting, manufacturers talked about their projected capacity and 

ACIP asked them to provide information at this February meeting. GlaxoSmithKline 

estimates that in 2007-8, there will be 35 to 40 million doses of the adult vaccine available, 

which is 10 million more than for the current season. About one-third of these are Influenza 

Virus Vaccine, Trivalent, Types A and B (Fluarix®), which has trace thimerosal and will 

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36

come from the Dresden facility. The other two-thirds are Influenza Virus Vaccine, Trivalent, 

Types A and B (FluLaval®), from the Canadian facility. FluLaval has thimerosal 

preservative and is sold in multidose vials. GSK is currently conducting studies of pediatric 

vaccine with trace thimerosal, and a thimerosal-free pediatric vaccine is under development. 

MedImmune makes Influenza Virus Vaccine, Live, Intranasal (FluMist®), a live attenuated 

vaccine, also known as CAIV-T, which is a thimerosal-free presentation and administered 

intranasally. For 2007-8, there will be about 7 million doses of FluMist. The vaccine is 

currently licensed only for 5- to 49-year-olds. Licensure for a younger age group might occur 

before next influenza season. Capacity could ramp up to as many as 20 million doses in 

2008-2009 and between 35 and 90 million doses after that. 

Novartis projects 45 million doses per year over the next three to five years. They plan to 

shift most production to preservative-free vaccine and are expanding their influenza vaccine 

capacity, using cell culture-based influenza vaccines, with the possibility of limited quantities 

as early as 2008 and up to 50 million doses possibly available by 2012. A significant 

percentage of the cell-based vaccine will be preservative-free. 

Sanofi pasteur provided no new information, but a statement at the last meeting read as 

follows: "A new enclosed facility is under construction that will double sanofi pasteur’s 

capacity in 2008-9 and allow for production of 100 million doses of influenza vaccine. In 

2007 or 2008, sanofi pasteur expects to build a new fill-and-formulation facility that would 

allow for an expansion over the 8 to 9 million doses of preservative-free vaccine.” 

In summary, taking into account that these projections are subject to change based upon strain 

characteristics, what strains are chosen, licensure issues, production issues, etc., there could 

be as many as 130 million doses available for the upcoming influenza season. Twenty million 

of these could be preservative-free doses, but only one manufacturer is currently licensed to 

supply preservative-free TIV to young children; the LAIV is a thimerosal-free option for 

children over the age of five right now, with pending licensure for lower ages. Over the next 

three to five years, taking all of the manufacturers' projections together, there could be as 

many as 150 to 200 million doses, and manufacturers hope they will have increased 

preservative-free capacity. 

Dr. Fiore then discussed the current ACIP statement and changes proposed for the upcoming 

ACIP statement. There are four key issues for the 2007 recommendations. First, vaccine 

composition would be decided at the VRBPAC meeting on February 28th, after ACIP. That 

section of the statement will have to change if composition is changed. Second, the use of 

adamantanes should continue to not be recommended because of the greater than 30 percent 

resistance still present among H3N1 strains in the U.S. this season. Third, there's a change for 

children ages six months to less than nine years who received a single dose during their first 

year of vaccination instead of the recommended two doses: these children would receive two 

doses in their second year of vaccination. Finally, the age groups and the risk groups for 

whom routine vaccination is recommended has not changed, even though there has been some 

rearranging of the text and wording changes. 

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37

To improve readability and usability, the recommendation has been reorganized, starting with 

a summary and followed by the core of the recommendations. A new methods section 

describes studies and how they were selected and used to make recommendations. 

Effectiveness and safety are considered separately for TIV and LAIV, and results from new 

studies comparing TIV versus LAIV are presented. Recommendations on how individual 

vaccinators and immunization programs should give the vaccine and the antiviral section at 

the end have been expanded. 

The core of the recommendations reads as follows: "Vaccination is recommended for any 

person who wishes to reduce the likelihood of becoming ill with influenza or transmitting 

influenza to others should they become infected, depending on vaccine availability. Healthy, 

non-pregnant persons ages 5 to 49 can choose to receive either trivalent, inactivated 

influenza vaccine or live attenuated influenza vaccine. All others should receive TIV." 

 

The recommendation that anyone who wishes the vaccine should be vaccinated has been there 

for the last couple of years, but now is highlighted. There's no preference in this year's 

recommendations for TIV versus LAIV. The second part of the recommendations has the 

groups recommended for TIV; it reads as follows: 

"All persons in the following groups should receive annual influenza vaccination with 

TIV. Vaccination efforts should focus on delivering vaccination to these persons as well as 

contacts or caregivers of children less than six months old if vaccine supply is limited. 

 

 "All children aged 6 to 59 months old, all persons aged greater than 50, children and 

adolescents who are receiving long-term aspirin therapy; women who will be pregnant during 

the influenza season; adults and children with a variety of chronic conditions listed here; 

adults and children who have immunosuppression; adults and children who have any 

condition that compromises respiratory function and the handling of respiratory secretions or 

that can increase the risk for aspiration; and, finally, residents of nursing homes and other 

chronic-care facilities. 

"In addition, to prevent transmission to persons such as those identified above, all 

persons in the following groups should receive annual influenza vaccination with TIV or 

LAIV unless contraindicated: First healthcare workers. Secondly, healthy household 

contacts (including children) and caregivers of children who are 0 to 59 months of age and 

adults greater than 50 years of age; and healthy household contacts (including children) and 

caregivers of persons with medical conditions that put them at higher risk for severe 

complications from influenza.” 

The main change is "including children" because it has not been well understood that child 

contacts are an important group. It includes older children living with younger siblings, older 

folks, and/or other people with the variety of different chronic conditions that can lead to 

severe influenza. 

Dr. Fiore then drew attention to a change regarding children ages six months to less than nine 

years who received only one dose in their first year of being vaccinated. In the 2006 

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38

recommendations, it was clearly stated that all children ages six months to less than nine years 

who were getting vaccinated for the first time should get two doses. But inevitably, some of 

these children only got one dose in that first season. The issue was whether these children 

should get two doses or one dose in their second year. In the June 2006 meeting, both 

published and unpublished data were presented on this topic. At that time, the ACIP work 

group recommended and the ACIP agreed that the data were not sufficient to determine if one 

or two doses should be given to these children; one dose was recommended for a variety of 

different reasons, including feasibility. 

However in October 2006, the AAP Committee on Infectious Diseases reached a different 

conclusion, looking at roughly the same data. The first paper, Englund, et al., in Pediatrics,

came to the conclusion that, when the Influenza B antigen was changed for the second season, 

children who had only received one dose in that first season of being vaccinated and then got 

one dose in the second season had a decreased immunologic response to the Influenza B 

antigen, compared to children who received two doses in that second season. Then a paper 

that looked at ILI-type outcomes, by Allison, et al., published in the Journal of Pediatrics late 

last year, concluded that, in consecutive seasons when the influenza vaccine antigens were 

unchanged, the effectiveness against ILI in the second season was significantly less for 6- to 

21-month-old children vaccinated for the first time who received one dose at both seasons, 

compared to the 6- to 21-month-old children who received one dose in their first season and 

two doses in the second season. 

Based on those papers and discussions with colleagues at AAP, looking at feasibility and 

vaccine supply issues, the work group concluded that ACIP should change its 

recommendation to harmonize with that of AAP. The new language proposed is: "The ACIP 

now recommends two vaccine doses for children aged six months to less than nine years who 

received an influenza vaccine for the first time in the previous season but who did not receive 

the recommended second dose of vaccine within that first season." 

Next Dr. Fiore turned to language about thimerosal in the statement: "No scientifically 

conclusive evidence has demonstrated harm from exposure to thimerosal preservativecontaining vaccine. Persons recommended to receive TIV may receive any age- and riskfactor appropriate vaccine preparation depending on the availability." Little has changed 

from last year, but several paragraphs review the evidence and reiterate the concern about the 

health impact of not vaccinating some groups, such as young children and pregnant women 

who are eligible for vaccination, because of concerns about thimerosal. 

Another new issue is a need to better emphasize and improve vaccination coverage among 

healthcare workers. The statement this year is slightly reworded from last year: "All 

healthcare workers as well as those in training for healthcare professions should be 

vaccinated against influenza annually. Facilities that employ healthcare workers should 

provide vaccine to workers by using approaches that maximize vaccination levels. Higher 

vaccination coverage levels would likely protect healthcare workers, their patients, and 

communities; improve prevention of influenza-associated disease and patient safety; and 

reduce disease burden. Influenza vaccination rates among healthcare workers should be 

regularly measured and reported." 

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39

 The recommendations note the new Joint Commission on the Accreditation of Health 

Organization regulations that require accredited organizations to offer vaccination and 

measure vaccination coverage among staff. Also noted are various professional organization 

proposals and state health-law requirements that healthcare workers be vaccinated or provide 

a written statement declining vaccination. There have been a number of comments that the 

recommendation needs to be even stronger, so a proposal is to add: "All healthcare workers 

should be offered vaccination, and those who refuse influenza vaccination for reasons other 

than medical contraindication should be required to provide a signed declination.” The 

Healthy People 2010 objective of 60 percent coverage is also noted, along with a reference to 

additional professional society recommendations and state regulations that require vaccination 

unless healthcare workers can provide written declination. 

Finally, Dr. Fiore addressed language making immunization programs and vaccinators more 

flexible in terms of getting late-season vaccine, and getting vaccine in settings that are not 

traditional. The section entitled "Timing of Organized Vaccination Campaigns" reads, 

"Vaccination clinics should be scheduled through December and later, if feasible, with 

attention to settings that serve children 6 to 59 months of age; pregnant women; and other 

persons aged less than 50 years at increased risk for influenza-related complications; persons 

aged 50 or greater; healthcare workers; and household contacts of healthy children age 24 to 

59 months; and persons at high risk, including children aged 0 to 23 months to the extent 

feasible. Planners are encouraged to develop the capacity and flexibility to schedule at least 

one vaccination clinic in December." 

 

 Some of the language is reminding individual providers when influenza seasons typically 

peak and emphasizing the benefit of providing vaccination throughout the season: "Vaccine 

should be administered starting in late September and October and should continue through 

January and beyond because influenza activity typically peaks in February or March in the 

majority of seasons. Healthcare providers should be alert to potential vaccination 

opportunities during all healthcare encounters, including diagnostic or minor surgical 

procedures, as influenza season approaches. And whenever influenza vaccine is available, 

office staff should advocate or offer vaccination whenever patients contact medical-care 

facilities, including during requests for services such as prescription refills or appointment 

requests." 

 Dr. Fiore repeated the recommendation against the use of amantadine drugs, which says, 

"Amantadine and rimantadine should not be used for the treatment or prevention of influenza 

in the United States until evidence of susceptibility to these antiviral medications has been 

reestablished among circulating Influenza A virus subtypes." 

 

Discussion

Dr. Baker hoped the media would pick up the message that providers should continue to 

vaccinate into December and January and noted that the language about the peak of the season 

should be in both statements, not just in the providers’ statement. Dr. Harry Hull said that 

since ACIP is now recommending two doses for children, the statement should be clear that 

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40

that second dose should be given even late into the influenza season because influenza viruses 

may be circulating until April or May and children need to have that benefit of the timing 

effect of two doses. Dr. Julie Morita said that as an AAP member and ACIP member, she 

welcomed the harmonization in the revaccination recommendation for children less than nine 

years of age because it makes it easier to educate providers. 

Mr. Rob Beck asked if the two-dose program for part of the target audience would change 

projections of the available supply of vaccines. Dr. Fiore replied that it is hard to know how 

many children just received one dose when they should have gotten the two doses. NIS data 

should help clarify that concern. 

Dr. Baker asked whether existing registries included influenza vaccination, because that 

would be a way of getting that data: one versus two doses. Dr. Fiore pointed out that a 

December 2006 MMWR publication looked at the six sentinel registries. Coverage ranged 

from 6 percent to 50 percent among the six registries. 

Dr. Duchin asked what the recommendation would be for a child under nine years of age who 

received one dose in the first season, didn't receive a dose or received one dose in the second 

season and is now coming in the third season, still under age nine. Dr. Fiore replied that such 

a situation had not been specifically addressed. Presumably this applies only to the second 

season of eligibility for vaccinations, so the recommendation would probably be just one dose 

in subsequent seasons. 

 

Ms. Stinchfield was interested in the timing of the school-age group. If ACIP recommends the 

vaccine for this fall, after clinics, hospitals, and health departments have already ordered, 

implementation could be difficult. Dr. Bocchini mentioned that the statement this year 

seemed to limit the two doses to just the second year after the child received one dose in the 

initial year. Dr. Abramson clarified that the two doses are only a one-time occurrence, so if a 

child got two doses in the second year, in the third year, it would go back to one. 

Dr. Morse was concerned that if the projection for 130 million dose capacity in 2007-2008 is 

solid and ACIP does not change the recommendations, there could be a lot of extra vaccine 

for the coming year.

Dr. Schaffner asked whether there was any truth to the rumor that VRBPAC might be 

considering adding a fourth antigen next year. Dr. Baylor responded that the issue of adding a 

second B strain comes up every year at the influenza VRBPAC. There will be discussions 

this time, but no vote. 

Dr. Schaffner then informed the group that the National Foundation for Infectious Diseases 

has launched an educational activity to make sure adults and children with diabetes get 

vaccinated against influenza. Last November, the NFID held a roundtable with 

representatives from more than 15 medical and public-health organizations and all agreed that 

improving immunization rates in this group is an important goal. The NFID is developing a 

comprehensive monograph to provide further details on specific strategies and models. It's 

available on the NFID Web site. Comments and suggestions are welcomed. 

This document has been archived for historical purposes.
41

Dr. Kristin Nichol, as chair of the National Coalition for Adult Immunization Advisory 

Committee, seconded the importance of enhancing influenza vaccine delivery to people with 

diabetes. Current immunization rates in this high risk group lag substantially below the 

national 2010 health goals. 

 

Dr. Wallace, CDC, doubted whether 130 millions doses would be made this year. Regarding 

the [vaccination of the 6-to-59 age group] last year, he did not believe there would be more 

vaccine available for those 0 to 18 years of age than there is currently this year. Dr. Margaret 

Rennels, GSK, said that the 130 million doses was a goal, not a promise. It is not known 

what strains will be chosen, what the yield will be, or if a plant may become contaminated or 

a fill line may go down. Dr. Marie Mazur said that CSL Biotherapies hoped to have its 

influenza vaccine in the market this year. Most of its production is thimerosal free, and there 

is also a thimerosal-free indication. 

Dr. Kathleen Coelingh from MedImmune asked whether the recommendation about timing of 

influenza vaccines was meant to be a prohibition on administering vaccine whenever it 

becomes available. 

Dr. Jon Temte, American Academy of Family Physicians, asked whether there was a cut off 

point after which CMS will not cover administration of influenza vaccine in a given year. 

PUBLIC COMMENT

 

Diane McGowan introduced herself as a board member of Families Fighting Flu, a nonprofit, 

volunteer-based organization made up of families and healthcare practitioners who have 

experienced first-hand the death of a child due to the flu or have had a child experience severe 

complications from the flu. She told the story of how her family had lost their healthy 15-

year-old son to influenza two years ago. She noted that there have been at least 15 pediatric 

deaths from influenza this season, some of whom were older, healthy, school-age children not 

within the current recommendation. She urged the ACIP to expand the current 

recommendation to include the new age group, so that more lives would be saved. 

Mr. Scott Lassiter said he believed that CDC and the pharmaceutical companies are ignoring 

data that indicate concerns and dangers regarding thimerosal, even though their goals are 

laudable. He quoted an expert epidemiologist who questioned the design and conclusions of 

studies presented at this meeting. He then recounted his son’s experience with mercury 

poisoning, urging the ACIP to consider removal of thimerosal from all vaccines. 

Ms. Lyn Redwood disagreed that there is no scientifically conclusive evidence that 

demonstrates harm from exposure to thimerosal-preserved vaccines. She mentioned over 20 

peer-reviewed toxicological studies published in highly credible journals since 1999, which 

document harmful effects of thimerosal in animals, primates, and humans at vaccine levels 

exposure. These articles were dismissed by today’s presenter as not being informative. 

However, Ms. Redwood argued that the discussion should not be about whether thimerosal 

causes autism, but is it appropriate to inject a known neurotoxin at levels in excess of federal 

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42

safety guidelines into pregnant women, infants, and children? There is the capability to 

produce thimerosal-free vaccines and she urged the committee to reconsider its 

recommendation. 

 

Mr. Gary Stein told the committee about the loss of his daughter five years earlier from 

complications of influenza. She was not vaccinated, as are millions of children and adults in 

the U.S. today. He urged the committee to help other families by recommending universal 

influenza vaccination. As a founding member of Families Fighting Flu, he applauded the 

decision to expand the pediatric recommendation last year up to 59 months and urged the 

committee to pass a universal pediatric, if not total universal, influenza vaccination 

recommendation. 

Ms. Karen Beauvais told the committee about her son, who received over 277 times more 

than the EPA's allowable amount of mercury in his infant vaccines and then plunged into 

regressive autism. After three years of receiving chelation therapy, he still tested very toxic to 

mercury. Arguing that thimerosal was a poison that should not be ingested by a pregnant 

woman or an infant, Ms. Beauvais implored the committee to change its policy before more 

families are impacted by autism. 

 

Dr. Deborah Wexler, representing 122 organizations, urged ACIP to immediately recommend 

universal childhood and school-aged children vaccination against influenza. This is needed to 

simplify the current targeted recommendation, sustain and build manufacturing capacity, and 

provide benefits to individuals by reducing morbidity and mortality, providing herd-immunity 

protection, and enhancing vaccine access for all who wish to be vaccinated. She read a 

statement in support of universal vaccination for all school-aged children and teens through 

the age of 18. 

 

LCDR Stephen Kay related the experience of his two children who were recovering from 

mercury poisoning. He read a statement from the family’s developmental pediatrician, Dr. 

Nathanson-Lippitt, which outlined her findings on the effects of heavy metal build-up in 

children, many of whom develop symptoms of autism. Lt. Cmdr Kay stated that he was not 

anti-vaccine, but pro safe vaccines, and urged the committee to remove both thimerosal and 

aluminum from vaccines. 

 

Dr. William Redwood, a front-line healthcare provider in a large emergency department, 

stated that in 19 years as a practicing physician he had never diagnosed anyone with sepsis or 

respiratory failure secondary to influenza. He felt the more important issue was proactively 

educating the public on common-sense ways to prevent transmission of a range of 

communicable diseases spread by direct contact. He added that he was seeing increasing 

skepticism toward ACIP, not only around influenza, but also other vaccine-related diseases, 

such as hepatitis B at birth. He felt parents were becoming increasingly skeptical about what 

they perceive as offering up their children for vaccine testing, giving rotavirus vaccine and 

intussusception as an example. He urged the committee to step back and regain the public's 

trust, and make reasonable recommendations for vaccine based on sound evidence. 

 

Dr. Rick Zimmerman expressed concern about the low rates of healthcare worker vaccination 

This document has been archived for historical purposes.
43

coverage. He had reached the conclusion that declination would create an enormous 

administrative burden and suggested that hospitals use EMTs or nurses to take the vaccine to 

the floors or provide incentives, such as a lottery for paid time off. 

 

Vote

Dr. Abramson asked if the committee wanted to pull out any of the recommendations for a 

separate vote, while Dr. Fiore reviewed all the recommendations on the slides. 

 

Dr. Hull said he thought the American Academy of Pediatrics had said that the two doses in 

the second year only applied to the second year of life. Dr. Joe Bocchini responded that since 

there was less opportunity for exposure to natural infection and the highest risk would be in 

the second year, the emphasis would be to provide two doses in the second year. Subsequent 

to that, there would be increased opportunity to be exposed to influenza naturally and perhaps 

less need for more than one dose. Dr. Hull said that since there were only data on the second 

year and in the spirit of being harmonized with the American Academy of Pediatrics, the 

recommendation for two doses should be restricted. 

 

Ms. Stinchfield pointed out that the sentence that reads "Vaccination is recommended for any 

person who wishes to reduce the likelihood of becoming ill with influenza or transmitting 

influenza to others should they become infected, depending on vaccine availability,"

essentially reads universal influenza vaccination. She suggested that a compromise might be 

to recommend it for any person, including school-aged children, so they are highlighted. 

 

Dr. Susan Lett thought clarifying language about the third season would be helpful for 

clinicians. It can say there are no data, but people are going to ask the question. 

 

Dr. Treanor felt there was no real reason to specify that vaccination should not begin until late 

September if the vaccine is available earlier. In addition, if making people sign a declination 

form is a waste of administrative time, then it should not be recommended. The more 

important question is whether declinations are actually an effective strategy for increasing 

vaccination rates. Dr. Abramson replied that in his experience they do increase rates and 

make people think about protecting themselves and their patients as well. Dr. Kathy Neuzil 

was in favor of including declinations as just one of a number of approaches that might 

maximize vaccination levels, rather than focusing on just one. 

 

Dr. Plotkin noted that the first part of the second paragraph emphasizes TIV and then 

underlines that contacts or caregivers of children less than six months of age should be 

vaccinated. It seems to be excluding live attenuated vaccine for caregivers or contacts of 

children under six months of age but in fact there isn’t any such exclusion. The 

recommendation should be rephrased. 

Dr. Abramson asked for further comments and when there were none, he asked those who had 

arrived late to declare whether they had conflicts of interest. 

 Dr. Dale Morse: no conflict. 

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44

 Dr. Kathy Neuzil: no conflict. 

 Dr. John Treanor stated that he had a conflict. 

Dr. Ciro Sumaya; no conflict. 

 

Dr. Abramson noted that the VFC vote would take place after the break. He then 

asked for a motion for adoption, which would include the minor suggestions that will be 

edited in later.

 

 Dr. Allos moved that the committee accept the recommendation. 

 Ms. Stinchfield seconded the motion. 

 Dr. Sumaya: In favor. 

 Ms. Stinchfield: In favor. 

 Dr. Neuzil: In favor. 

 Dr. Morse: In favor. 

 Dr. Morita: In favor. 

 Dr. Leiu: yes.

 Dr. Hull: yes. 

 Dr. Gilsdorf: yes. 

 Mr. Beck: yes. 

 Dr. Baker: conflict. 

 Dr. Allos: yes. 

 Dr. Abramson: yes. 

The motion passed. 

VFC Resolution on Influenza Vaccine Recommendations

Dr. Angela Calugar, CDC/NCIRD

Dr. Calugar presented the updated Vaccine For Children program (VFC) resolution related to 

influenza vaccines. The purpose of this resolution is to revise the previous resolution from 

February 2006 to recommend that children who received only one dose in the first year at 

vaccination should receive two doses in their second year at vaccination. 

There were no changes on the first page besides the purpose. On the second page, under 

Recommended Influenza Vaccine Schedule, the wording closely matches Dr. Fiore's initial 

recommendations, and this text will be updated to match it exactly with the final 

recommendation which ACIP voted on: "All children ages six months to less than nine years 

who receive influenza vaccine for the first time should be given two doses. Children who 

receive only one dose in the first year of vaccination should receive two doses in their second 

year of vaccination." There were no other changes to the VFC resolution. 

Discussion and Vote 

 

Dr. Jeff Duchin, representing NACCHO, asked whether VFC could provide vaccine to any 

child or parent who wished their child to be vaccinated in addition to the target groups, since 

the new recommendation and the old suggest that anyone who wishes to avoid influenza 

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45

should be vaccinated. He felt it would be difficult to carry out that recommendation if VFC 

restricts access to only those in the target groups. Dr. Calugar explained that this statement 

was in the previous resolution voted on February 2006. It implies that, if there is enough 

supply, all children aged 6 months to 18 years are eligible to receive influenza vaccine. Dr. 

Duchin asked whether that would be taken into consideration when VFC vaccine is allocated. 

Dr. Wallace responded that vaccine allocations are allocated based on available supply. VFC 

resolutions do not make vaccine. 

 

Dr. Hull asked whether the committee could vote before the changes in language were made. 

Dr. Wallace replied that the committee had the updated version, which reflected the new 

ACIP recommendation: "All children aged six months to less than nine years who receive 

influenza vaccine for the first time should be given two doses. Children who receive only one 

dose in the first year of vaccination should receive two doses in the second year of 

vaccination." 

 

Dr. Allos moved that the committee accept the language on the slide and adopt the VFC 

recommendation. The voting proceeded as follows: 

 Dr. Lieu: yes.

 Dr. Lett: yes. 

 Dr. Hull: yes. 

 Dr. Gilsdorf: yes. 

 Mr. Beck: yes.

 Dr. Baker: conflict. 

 Dr. Allos: yes. 

 Dr. Treanor: conflict. 

 Dr. Sumaya: yes. 

 Dr. Baker: yes.

 Ms. Stinchfield: yes. 

 Dr. Neuzil: yes. 

 Dr. Morse: yes. 

 Dr. Morita: yes. 

 Dr. Abramson: yes. 

 

The motion passed. 

Interagency Pandemic Influenza Vaccine Prioritization Workgroup Update

Dr. Ben Schwartz, National Vaccine Program Office (NVPO) 

Dr. Schwartz began his presentation by explaining that it was necessary to prioritize pandemic 

influenza vaccination because everybody is assumed to be susceptible to a pandemic virus, 

but the U.S.-based production capacity currently is not sufficient to make vaccine rapidly for 

the entire population and the earliest doses of pandemic vaccine currently are projected to 

become available about 20 weeks after identification of the pandemic virus. He illustrated the 

large gap between the current U.S. based capacity to produce influenza vaccine for a 

pandemic and what is projected as the national need, representing the entire U.S. population. 

Assuming that two doses will be required per person at 90 micrograms per dose, the pandemic 

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46

will spread much more rapidly than the amount of vaccine produced in an entire year. 

 

A number of government initiatives have been implemented, with over $1 billion going to 

increase vaccine production capacity, develop and license new pandemic vaccine production 

technologies, particularly cell-culture-derived vaccine, and evaluate adjuvanted vaccine 

formulations. Some results presented recently on the potential effectiveness of candidate 

H5N1 vaccine formulations suggest that adjuvanted vaccine formulations may allow the use 

of vaccine with more than 90 micrograms per dose. 

 

John Treanor's study suggests that 90 micrograms of unadjuvanted sanofi vaccine produced in 

the U.S. yielded a protective antibody response in 54 percent of vaccine recipients after two 

doses. By contrast, studies done with other vaccines suggest that, at lower antigen doses, 

similar or higher immune response can be achieved, although different assays and study 

population were used. The results reported in a press release by GSK have not yet been 

published in a peer-reviewed journal. These studies suggest that, as production capacity 

increases, it may be possible to stretch the number of doses made by using an adjuvanted 

formulation, thereby decreasing the amount of antigen needed in each dose. 

In the spring and summer of 2005, the ACIP and NVAC jointly evaluated the potential 

priority groups for pandemic vaccination, taking into consideration vaccine supply and 

efficacy, the impacts of pandemic disease by age and risk group, potential impact on critical 

infrastructure and on healthcare, and the ethical basis for pandemic vaccine prioritization. 

Recommendations adopted unanimously by both of these advisory committees are included in 

the 2005 HHS Pandemic Plan and provide guidance for state and local planning. 

Many of the same groups recommended for annual vaccination are included in the highest 

priority tier for pandemic vaccination, including healthcare providers, high-risk groups, 

household contacts of young infants, immunocompromised people, and pregnant women. In 

fact, it is not until over 100 million people have received vaccine that critical infrastructure 

outside of healthcare is recommended for prioritization. 

The committees considered the goal of mitigating adverse health outcomes in a pandemic as 

being above mitigating societal and economic impacts. The pandemic severity assumptions 

used were based on a 20 to 30 percent attack rate and a case fatality rate of up to 1 percent. 

The committees also emphasized the certain benefit associated with vaccinating high-risk 

individuals versus the unclear benefit of vaccinating people in critical infrastructure sectors. 

Absenteeism due to illness or caring for family members at the peak of a community outbreak 

was estimated at 10 to 15 percent and the committee recognized the data suggesting a much 

greater mortality risk among vulnerable persons than others in the general population. 

Since the recommendations were made a year and a half ago, there have been a number of 

reasons why they should now be reconsidered. A set of public engagement meetings 

coordinated by CDC at the end of 2005 identified preserving essential services as the most 

important goal for the public and stakeholders who participated in these meetings; protecting 

those at high risk of severe influenza disease rated second. National planning assumptions 

now assume a more severe pandemic, based on extrapolation from 1918, with a 2 percent case 

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47

fatality rate, and assumptions on absenteeism are up to 40 percent, based on additional 

absenteeism if schools are closed and people need to care for their children or are reluctant to 

go out or to work. Pandemic response strategies have evolved, such as the communitymitigation guidance that CDC put out earlier this year, and there has been additional analysis 

of critical infrastructures. 

The priority groups for pandemic vaccination are being reconsidered by a working group 

made up of several federal agencies. The process involves presentations on key issues by key 

stakeholders from public health and from Homeland Security, consideration of ACIP and 

NVAC recommendations and National Infrastructure Advisory Council (NIAC) 

recommendations on critical infrastructure, results of public engagement and stakeholder 

meetings, a decision-analysis process, and written comments in response to a request for 

information. 

The NIAC analysis of critical infrastructure for a U.S. pandemic looked at functions of critical 

infrastructure in key resource sectors, which included maintaining national and homeland 

security, ensuring economic survival, and maintaining health and welfare. The committee 

considered the interdependencies among sectors and the work force needed to retain the most 

critical functions and activities. The process included surveys of operators within these 

various sectors, a review of existing data and plans, and interviews with subject-matter 

experts. The results of the NIAC analysis are available on the Department of Homeland 

Security Web site. Overall, NIAC identified critical workers in three tiers with almost 17 

million workers. The largest group is healthcare followed by emergency services and 

information technology. Employees who are most essential to providing the most critical 

functions in each of these sectors numbered 12.4 million, three-quarters of those in healthcare 

and emergency services sectors. 

 To summarize, as a proportion of the entire critical infrastructure work force of 85 million 

people, the top tier represents only about 141⁄2 percent and all three tiers only about 20 percent 

of the work force. When expressed as a proportion of the entire U.S. population, the first tier 

is about 4 percent of that population and all three tiers about 51⁄2 percent. Excluding 

healthcare and emergency services, the proportions are relatively small. When ACIP and 

NVAC considered critical infrastructure, estimates were 9 million individuals in healthcare 

and emergency services and about 9 million people in the other sectors, so NIAC's estimates 

are actually more parsimonious. 

 Recent public-engagement and stakeholder meetings have provided important input regarding 

prioritization. Participants in Las Cruces, New Mexico included over 100 persons of 

culturally diverse backgrounds, a large portion of whom were Spanish-speaking. A second 

public-engagement meeting in Nassau County, on Long Island, New York, had 130 people, 

many of whom were older individuals. In fact, from both public-engagement meetings 

together, 31 percent of the population was 65 years of age or greater. The stakeholder meeting 

in Washington, D.C., included representatives of about 90 different government and 

community organizations and critical infrastructure sectors. 

 A severe 1918-like pandemic was assumed, but there was no assumption of increased 

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48

mortality among young, healthy individuals, as occurred during 1918. Uncertain vaccine 

timing and supply was assumed, and vaccination was considered in the context of other 

pandemic-response measures, including border strategies to delay the pandemic, community 

mitigation strategies to decrease impact, antiviral treatment and prophylaxis, as well as 

planning by government and businesses. 

 The 10 potential goals for a pandemic vaccination program basically include occupational 

function and occupational risk, as well as the potential risk among various groups of the 

general public. Participants were asked to rate the goals on a seven-point scale. The highest 

rated goal was to protect people working to fight the pandemic and provide care for those 

with pandemic illness, followed by those who provide essential community services, then 

children and those who are most vulnerable to infection due to their jobs. Interestingly, people 

who are most likely to get sick or die did not rate as highly in any of the meetings. 

To summarize, the highest rated goals were the same in all of the meetings. The values 

underlying those goals included the importance of maintaining critical societal functions; 

protecting those who would help others during the pandemic; and protecting children, who 

represent the future. The key message seems to be the importance of balancing and 

simultaneously considering multiple purposes for pandemic vaccination. 

The working group has drafted prioritization guidance. Once it becomes available, one to two 

months are anticipated to get comments from additional public and stakeholder meetings; 

from a Web-based, public-engagement process; written comments; as well as ACIP and 

NVAC input. The guidance should be finalized before the June ACIP meeting. The working 

group also will be considering pre-pandemic vaccine prioritization and the approach to 

modifying guidance at the time of a pandemic once the severity and epidemiology of disease 

is known. 

Discussion

Dr. Baker asked where a woman who is 34 weeks pregnant would fall in these groupings. If 

children are being valued, then the death of the mother would be a severe threat to the baby. 

Dr. Schwartz replied that was important to balance the needs of national and homeland 

security, critical infrastructure, pandemic response, and the needs of vulnerable populations. 

 

Dr. Allos commented that the only other time vaccine recommendations were taken away 

from the ACIP and given to other federal agencies was with smallpox. She then noted that it 

is tricky to assign priorities because it appears to assign value to different people’s lives. In 

addition, she worried that saying vaccine should be given to transportation workers could 

become enormously complicated, for example, proving someone is a truck driver and 

deciding which truck drivers to vaccinate. Finally, she asked about estimates as to how long 

the absenteeism might be as high as 20 or 40 percent and what the preparations were for such 

a contingency. Dr. Schwartz replied that high absenteeism would probably be only a couple 

of weeks out of an 8- to 12-week outbreak. The community-mitigation guidance suggests 

closing schools for 12 weeks, so that already means 10 percent of the work force is likely to 

be absent for that three-month period. Regarding giving this guidance to other federal 

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49

agencies, Dr. Schwartz explained that many different sectors have a stake in pandemic 

influenza vaccination and prioritization, especially critical infrastructure sectors such as 

Homeland Security or the Department of Defense. A working group representing the various 

departments increases involvement and buy-in to the results of the process. ACIP will be 

asked for comments and endorsement of the final guidance. 

Dr. Plotkin suggested that the ACIP might consider a recommendation to immunize the 

population with an H5N1 vaccine now. There are data indicating that the current strains 

would make good vaccines even if there is more mutation of the H5N1. A recommendation 

from ACIP would stimulate manufacturers to make a vaccine and consider putting a fourth 

strain into the vaccine. 

 

Dr. Rennels asked what was meant by pre-pandemic vaccine prioritization -- is it 

prioritization before the pandemic, or stockpiling or vaccinating before the pandemic? Dr. 

Schwartz replied that it refers to the vaccine made before a pandemic against strains with 

pandemic potential, and so it would include stockpiled H5N1 vaccine, for instance. He said 

the working group would be providing guidance on prioritization of this vaccine, but not be 

making recommendations for a particular strategy for when or how it's used. Dr. Baylor 

added that there would be a discussion at the next VRBPAC about the licensure of an H5N1 

vaccine. As part of that, VRBPAC would discuss prime boosting as well as cross-protection 

and other strategies for immunization against a potential strain. 

 

Dr. Zimmerman expressed concern that there may not be enough vaccine for the large 

numbers of people within the prioritized groups, particularly in the first few weeks or few 

months, and that vaccine might just go to the most advantaged, the best informed, and the 

richest. He noted that in a time of polio-vaccine shortage, Britain used a lottery. 

 

Dr. Foster asked how long the vaccine will last in storage and whether there was possibility of 

using it up before it expires in storage. Dr. Baylor said the FDA was looking at stability, date, 

and duration of protection. Dr. Gellin further clarified that the majority of stockpiled vaccine 

remains in bulk, so that the required dose could be formulated at the time it is needed. New 

science would potentially allow it to be formulated through an adjuvant, even if there has 

been a loss of “potency” over time. 

Review of Safety Data on Influenza Virus Vaccine, Live, Intranasal (FluMist®)

Dr. Robert Walker, Vice President, Clinical Development, MedImmune

Dr. Abramson reminded the committee that efficacy data had been presented in October and 

that the New England Journal of Medicine had a report about the cold-adapted influenza 

vaccine and its efficacy and safety. There is an application before the FDA to expand its use 

down to one year of age and ACIP may vote on recommendations in June. 

 

Dr. Walker presented a comprehensive safety summary for children within the proposed 

indication, as well as relevant data for children outside the proposed indication, to assist the 

members of the committee in developing recommendations for FluMist. The AV019 or Kaiser 

study was a placebo-controlled trial, conducted in over 9,000 children, 1 to 17 years of age. 

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50

In pre-specified safety analyses, a signal for asthma/reactive airways disease, a coded 

diagnostic term in the HMO database, was initially found in children 18 to 35 months of age 

within 42 days of vaccination, where the rates were 2.2 percent in FluMist and 0.45 in 

placebo. In post-hoc analyses conducted to better understand the signal, an increased risk 

through 59 months of age could not be ruled out. For children 12 to 59 months of age, the 

rates were 0.69 in FluMist and 0.20 placebo. 

The medical visits for asthma/RAD were not temporally clustered within the 42-day period. 

There were no hospitalizations, and most of the visits were associated with standard 

medication use. There was no increased risk in children five years of age and older. In fact, 

rates of asthma/RAD were significantly decreased in some analyses of older children who 

received FluMist versus placebo. A limitation to the Kaiser study was that it was not 

prospectively designed to specifically assess the risk of asthma. Nonetheless, based on the 

observations from this study, MedImmune decided not to seek initial approval for FluMist in 

children under five, pending additional study. 

Soon after the initial approval of FluMist, MedImmune undertook the CP111 pivotal study to 

evaluate safety and comparative efficacy in children under five. CP111 was a randomized, 

double-blind, multinational study that used an active control of injectable influenza vaccine, 

or TIV. It enrolled 8,475 children who were 6 to 59 months of age. All children, including 

those with underlying medical conditions, were eligible to participate except those with recent 

wheezing, severe asthma, or immune compromise. The primary endpoint was the relative 

efficacy of FluMist versus TIV against culture-confirmed modified CDC influenza-like 

illness, or CDC ILI. For the purposes of the protocol, modified CDC ILI was defined as fever 

plus either cough, sore throat, or runny nose and nasal congestion. 

Since an important safety objective was to further investigate the asthma/wheezing signal 

identified in the Kaiser study, CP111 used a prospectively defined safety endpoint termed 

"medically significant wheezing" or MSW. This endpoint required a medical diagnosis of 

wheezing associated with other respiratory findings or with initiation of bronchodilator 

therapy. 

All children received their first vaccinations by the end of October. With the onset of 

influenza circulation more than two months later, the proportion of children with influenza 

was statistically significantly reduced in the FluMist group compared to the TIV group. 

Overall, for the season, there were 338 cases in TIV and 153 cases in FluMist, representing a 

55 percent reduction in influenza cases caused by any matched or mismatched strain in 

FluMist compared to TIV. 

For the standard safety comparisons, rates of serious adverse events were similar in the two 

treatment groups and rates of reactogenicity events were as expected. FluMist recipients had 

more runny and stuffy noses, and TIV recipients had more injection-site reactions. For the 

pre-specified safety endpoint of medically significant wheezing, there was no increased risk 

observed in FluMist recipients among those children two years of age and older. A 

statistically significant increase was seen, however, in children under two years of age in the 

two-dose group within 42 days after Dose 1, where the incident rates were 3.2 in FluMist and 

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51

2.0 in TIV. This increase after Dose 1 in children under two years of age occurred primarily 

among children ages 6 to 11 months. 

 

In terms of severity of MSW, the proportion of children under 24 months of age with MSW 

who had tachypnea, dyspnea, retractions, or hypoxemia within 42 days after Dose 1 was 

similar: 27 percent for FluMist, 26 percent for TIV. Twelve children were hospitalized with 

MSW within 42 days after a dose: 0.5 percent of all FluMist recipients and 0.2 percent of all 

TIV recipients in this age group. No child was treated in an ICU or received mechanical 

ventilation, and there were no deaths because of MSW. Children in the two treatment groups 

who were hospitalized with MSW appeared to have comparable illness severity based on the 

length of hospital stay, discharge diagnoses, and treatment received in the hospital. 

Recurrences of MSW were also examined. Children with at least one additional MSW 

episode or with two or more episodes were balanced between the two treatment groups. Thus 

there was no evidence that children with MSW post vaccination with FluMist were 

predisposed to subsequent episodes of MSW compared to children who wheezed post 

vaccination with TIV over the approximately seven months of follow up on the study. 

After completing the planned analysis of the study data, a post-hoc risk-benefit analysis was 

conducted. The objective was to evaluate both safety and efficacy endpoints over the same 

time interval, extending from first vaccination through 180 days after the last vaccination. 

Endpoints included protection from influenza, that is, culture-confirmed, modified CDC ILI, 

as well as medically significant wheezing and all-cause hospitalization. The risk-benefit 

endpoints were analyzed by grouping according to whether they had a prior history of 

wheezing or asthma. Base prior-history information was obtained at the time of screening and 

was based on responses by the parent and medical staff to two questions: Does the subject 

have a past medical history of wheeze? Has a diagnosis of asthma ever been made?

 The results of the risk and benefit analysis for FluMist versus TIV for the 6500 children in the 

study without a prior history of wheezing or asthma were reported. In the youngest age subset, 

children 6 to 11 months of age, a statistically significant benefit was seen for flu prevention. 

Twenty-nine fewer cases of influenza resulted for every 1,000 children vaccinated with 

FluMist versus TIV. This benefit, however, was offset by risk of MSW -- 19 more cases per 

1,000, though not statistically significant -- and by risk of all-cause hospitalization: 34 more 

cases per 1,000, which was statistically significant. Based on the increase in hospitalizations 

for this age group, MedImmune is not seeking an indication in children under 12 months of 

age. Further study in this age group is needed to determine whether FluMist caused these 

hospitalizations, most of which were common pediatric diagnoses occurring over 42 days post 

vaccination. 

In each of the four older age subsets, a statistically significant benefit for flu prevention was 

seen, despite the fact that the study was powered to demonstrate statistical significance only 

across the entire population of 6 to 59 months. In contrast to what was observed for the 

youngest children, the trends for MSW and all-cause hospitalizations were generally in the 

direction of benefit although this was not statistically significant. Only in the 12- to 23-month 

subset was there evidence of some low risk of MSW. Four cases per 1,000 were observed, 

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52

which is in contrast to the benefits seen in terms of reduction in influenza, 35 fewer cases per 

1,000, and reductions in hospitalizations, 8 per 1,000 in children treated with FluMist vs. TIV. 

 For the group of children 12 to 59 months of age without a history of wheezing or asthma, the 

overall risk-benefit profile for FluMist appeared highly favorable. Based on these findings, 

this is the population for which MedImmune is seeking an expanded indication for FluMist. 

The risk-benefit for the remaining 1700 children in the study who had a prior history of 

wheezing or asthma was also assessed. Despite smaller numbers in this group, the benefit for 

influenza prevention was statistically significant for children in the 12- to 23- and 24- to 35-

month subsets. For children with a history of wheezing or asthma, non-statistically significant 

trends towards increased MSW and increased hospitalizations were seen for all but the 48- to 

59-month subset. Although this risk profile was not associated with statistical significance 

and so is different from hospitalizations in children 6 to 11 months of age, these trends 

suggest a need for caution. Therefore, until further studies are available, MedImmune is not 

seeking an indication in children under 59 months of age with a history of wheezing or 

asthma. 

 CP111 was designed as a pivotal efficacy and safety trial, and the number of children 

evaluated was quite large. However, CP111 was one of 13 studies in young children included 

in the safety summary provided to the FDA in support of the proposed expanded indication. 

These 13 trials provided safety information on more than 30,000 children 6 to 59 months of 

age. Nine were placebo-controlled studies and accounted for more than half of the children 

whose data were summarized. Three studies were TIV controlled, and CP111 contributed 

most of the children in this category of studies. One study was uncontrolled. In a safety 

summary provided to the FDA, these trials provide data about rates of serious adverse events. 

Nearly all SAEs were hospitalizations. The analyses of these studies included all children 

regardless of history of wheezing or asthma. 

 In the nine placebo-controlled trials, rates of serious adverse events through 180 days after 

last vaccination were assessed for the 12,000 children 12 to 59 months of age. SAEs included 

wheezing, pneumonia, and gastroenteritis, which were selected because of the findings from 

CP111 regarding medically significant wheezing and hospitalizations where lower respiratory 

tract and gastrointestinal infections were the most common diagnoses. Across the nine 

placebo-controlled trials, rates of SAEs were nearly the same for FluMist recipients as for 

placebo recipients for all four categories of SAEs analyzed. 

 In children 6 through 11 months of age, rates of SAEs were higher than in the older children, 

but rates in FluMist recipients were generally lower than those in children in the placebo 

group. For pneumonia SAEs, rates were comparable for FluMist and placebo, thus the 

observation from CP111 regarding hospitalizations in FluMist recipients compared to TIV 

recipients in this age group was not seen in the combined SAE analyses of the placebocontrolled trials. 

Finally, there are data from a recently published head-to-head comparative study of FluMist 

and TIV in asthmatic subjects 6 to 17 years of age. While children with asthma are currently 

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53

excluded from the label, these are the only data from a large comparative trial that directly 

address safety of FluMist in children with chronic underlying lung disease. Asthma 

exacerbations in this study, assessed within 42 days after vaccination, occurred at similar rates 

in TIV and FluMist recipients. This was true when looking at all exacerbations as well as 

specific categories of exacerbations, including hospitalizations, unscheduled clinic visits, and 

increased asthma medication use. Thus there was no evidence from the study that receiving 

FluMist resulted in worsening asthma control compared to TIV over the six weeks following 

vaccination. 

 In conclusion, in the CP111 study, FluMist demonstrated superior efficacy against both 

matched and mismatched influenza strains compared to TIV. Although not discussed in 

today's presentation, high efficacy for FluMist has also been demonstrated in six large 

placebo-controlled trials. The safety of FluMist for children less than 12 months of age and in 

the children less than 59 months of age with a history of wheezing or asthma needs further 

study. In children 12 to 59 months without a history of wheeze or asthma, FluMist appears to 

have a highly favorable risk-benefit profile. Approximately 80 percent of the children 

between 12 and 59 months in CP111 fit this description. Review of placebo-controlled trials 

supports the safety of FluMist in children 12 to 59 months. Data to support the proposed 

indication in children 12 to 59 months without a history of wheeze or asthma are currently 

under regulatory review. 

 

Discussion

Dr. Abramson asked how the children with history of wheezing or asthma had been chosen. 

He wondered if any had developed a history of wheezing in between the first and second dose 

and if so, of those who were hospitalized, how many were actually hospitalized for wheezing 

versus other non-related reasons? Dr. Walker responded that overall the rate of 

hospitalization for MSW was very low, 0.5 and 0.2 percent. Chart reviews revealed that half 

of the children had a prior history of wheezing and half did not. However, the majority of 

children hospitalized in this study were hospitalized with common pediatric problems, mostly 

gastroenteritis, oftentimes rotavirus gastroenteritis and lower respiratory tract and upper 

respiratory tract infections. 

 

Dr. Neuzil asked whether the population included in the CP111 study was all vaccine naïve, 

or could they have had prior vaccination? Dr. Walker replied that they stratified based on 

whether or not the children had been previously vaccinated or not. About 20 percent had been 

previously vaccinated and 80 percent of those were in the two-dose group. Dr. Neuzil asked 

whether this made any difference in the analysis of the medically significant wheezing. In 

other words, since the first dose is the concern, did having had a prior vaccination mitigate the 

wheezing? Dr. Walker responded that the data seemed to indicate it was an age-related 

phenomenon and not prior vaccination, and that it was related to a history of asthma or 

wheezing, regardless of whether they were in the one-dose group or the two-dose group. Dr. 

Neuzil noted that the youngest children would have had fewer opportunities to receive a dose 

of vaccine and then asked about the large time interval of 180 days. If broken up in smaller 

time intervals, was any effect closer to the vaccine seen? Dr. Walker replied that the 

hospitalizations were mostly late-occurring events, beyond 42 days; 180 days was chosen as a 

This document has been archived for historical purposes.
54

way of standardizing and representing most of the influenza surveillance period that was 

assessed. Most of the hospitalizations were really the late-occurring events. Dr. Neuzil went 

back to the question of how well past history can be identified in a population beforehand. It 

appeared that parents were asked about recent wheezing or severe asthma, but then the charts 

were used for the post-hoc analysis. Dr. Walker replied that what was used was a composite 

of both what the parent provided and what the medical team provided. 

 

Dr. John Iskander reminded the committee that post-licensure safety data jointly published by 

CDC and FDA in JAMA a little over a year ago indicated that, among episodes of wheezing 

reported in post-licensure safety surveillance, the primary risk factor was prior history of 

wheezing. He also wondered about the reliability of using either history or chart review to 

identify a prior history of wheezing illness, given that alternate, nonstandard terms like 

bronchitis are sometimes used to hide or obfuscate diagnoses such as asthma. Dr. Treanor 

added that this also raised the question of whether those who analyzed the charts could 

determine whether or not the subject had actually developed MSW during the trial. 

 

Dr. Treanor asked whether the Wyeth trials involved children this young. Dr. Walker replied 

that most of the placebo-controlled trial data reviewed came from some of the Wyeth studies 

involving children typically 6 to 35 months of age. Dr. Treanor noted that Wyeth also did 

comparative trials with TIV and those studies did not show an increase in wheezing. Dr. 

Walker added that one of those studies was the TIV/FluMist comparative study in 6- to 17-

year-old asthmatics. Another study, similar in design but in younger children with a history 

of recurrent respiratory tract infections, also showed superior efficacy and no increase in postvaccination wheezing. Dr. Treanor wondered if the variability between studies appearing to 

show an association with wheezing and other studies not showing an association could 

potentially reflect strain-to-strain differences in the reassortants from year to year. Dr. Walker

replied that the two studies, AV019 and CP111, were conducted in different populations of 

children, in different years, so they did have different vaccine strains. 

 

Dr. Morse asked whether, using a composite history of wheezing from the parents or the 

doctor, it was possible to determine which was more important for the association. Dr. 

Walker replied that they were additive and that the best ability to isolate the risk was based on 

information from both the parent and the physician rather than one or the other. 

 

Dr. Abramson reminded ACIP members that they would be asked to make a recommendation 

for a vaccine that has better efficacy, but has increased risk for wheezing and hospitalization 

in those with a history of wheezing. He asked if there were any questions now for which 

answers could be brought to the June meeting. 

Dr. Jon Temte, American Academy of Family Physicians, wondered if any of the analysis was 

done looking at children for whom the definition of wheezing or asthma was based on past 

use of medication for wheezing or asthma, and whether that was broken out as a definition. 

Dr. Walker replied that the information related to wheezing collected from the Kaiser study 

included medication use. However, on CP111, a yes or no response from parents was 

adequate to differentiate children with and without the risk. 

 

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55

Dr. Treanor wondered how severe the MSW really was and whether the children who 

developed it after the first dose received the second dose anyway. Dr. Walker replied that 

about 40 percent of children who wheezed after the first dose went on to receive the second 

dose. Most did not wheeze with the second dose. 

 

Dr. Abramson asked if anyone in the public wanted to speak. There was no response, so the 

meeting was adjourned at approximately 5:09 p.m. 

Friday, February 22, 2007 

UNFINISHED BUSINESS

The second day began with finalizing the hepatitis A post-exposure recommendations, carried 

over from the previous day. Dr. Bell went over the revised wording for this draft 

recommendation. The current ACIP recommendation for post-exposure prophylaxis says to 

use IG as soon as possible after exposure. Vaccine, if also recommended, can be given at the 

same time. The current wording further states that the results of a clinical trial comparing 

vaccine and IG are needed to determine if vaccine alone can be used. 

Dr. Bell recalled that the previous day there was discussion about current recommendations 

for pre-exposure use of hepatitis A vaccine, which include all children ages 12 to 23 months; 

catch-up vaccination of older children in areas with existing programs, with some permissive 

language for other parts of the country; persons at increased risk, including travelers, people 

with chronic liver disease because of the risk of more severe consequences, and men who 

have sex with men and illicit drug users. 

The randomized clinical non-inferiority trial conducted in Kazakhstan found that hepatitis A 

vaccine efficacy was similar to that of IG, that is, the non-inferiority criterion was met. 

Because of the study design, the point estimate for vaccine efficacy required an assumption 

about IG efficacy. Assuming 90 percent IG efficacy, the point estimate of vaccine efficacy 

was 86 percent with a 95 percent confidence interval of the upper bound of the relative risk of 

76 percent. If 85 percent IG efficacy is assumed, the point estimate of vaccine efficacy was 

80 percent with the upper bound of 64 percent. The proportion of outcomes among vaccine 

recipients was slightly higher than among IG recipients, although not statistically so. Putting 

this in context, the risk of hepatitis A among vaccine recipients was never more than 1.5 

percent greater than among IG recipients. The study provided evidence, consistent with many 

previous studies in IG recipients, that IG might attenuate clinical illness when given after 

exposure. 

Dr. Bell enumerated a number of reasons why one might want to be able to use hepatitis A 

vaccine post exposure. It offers a number of advantages over IG and provides the flexibility 

to use the vaccine in some circumstances post exposure where it might be quite beneficial. 

But not all populations were studied in the post-exposure clinical trial, most importantly, 

people over 40 years old and people with medical conditions. This trial took a number of 

years to complete. The number of index cases of hepatitis A recruited is now equivalent to 

about a third of all U.S. hepatitis A cases reported in a year. It won’t be possible to answer the 

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56

remaining questions about populations not studied in this clinical trial because no further data 

are expected with respect to use of vaccine alone post exposure. 

The proposed wording for patients with chronic liver disease and immunocompromised 

persons indicates a preference for IG. This is predicated on the fact that these populations are 

known to have a poorer response to vaccine pre-exposure. Also, chronic liver disease patients 

appear to have more severe outcomes and a higher risk of death following hepatitis A. 

For persons older than 40 years or not considered “healthy”, the draft wording simply states 

that there are no data. The rationale behind this proposed wording is that there's little 

information in the pre-exposure literature one way or the other and little information on which 

to base a preference for IG. 

Another issue was what can be learned from those countries that have been using vaccine for 

three to six years. Vaccine is essentially all that is used in Canada and IG is very difficult to 

get there. Dr. Naus polled people around the country and received one report of what 

appeared to be a chain of transmission in a couple of child day care centers and a household in 

late 2003/early 2004, where there might have been some breakthrough infections. In the 

U.K., most people are thought to be using IG and vaccine - some are using mostly vaccine, 

and some are using IG. She had no information with respect to the performance of vaccine. 

They have only 700 or 800 hepatitis A cases a year and so they would not be in a position to 

ascertain breakthrough infections with any regularity. 

A group called the Viral Hepatitis Prevention Board provides information about viral hepatitis 

in Europe. Their survey indicated that three countries in Western Europe use vaccine alone, 

while most other countries are using both vaccine and IG. They were not aware of any 

particular concern one way or the other about the use of vaccine in a post-exposure setting. 

 

 Dr. Bell went over the rewritten wording: 

"Unvaccinated persons who recently have been exposed to HAV should receive a single dose 

of vaccine at the age-appropriate dose for pre-exposure use or IG as soon as possible. The 

efficacy of IG or vaccine, when administered more than two weeks after exposure, has not 

been established. For people who receive vaccine, the second dose should be administered 

according to the licensed schedule to complete the series. 

IG should be used for children less than 12 months old, for immunocompromised persons, for 

persons who have been diagnosed with chronic liver disease, and for persons for whom 

vaccine is contraindicated. Persons administered IG, for whom hepatitis A vaccine is also 

recommended, should receive a dose of vaccine simultaneously with IG. The post-exposure 

efficacy of hepatitis A vaccine in persons less than two years or greater than 40 years and 

persons with medical conditions has not been studied." 

 

Discussion 

Dr. Allos wondered if the sentence that begins "Efficacy of IG or vaccine has not been 

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57

established," might be misinterpreted to mean that vaccination might not be effective, period, 

not just for post-exposure prophylaxis. Dr. Bell said this sentence was lifted directly from the 

current statement with the addition of "or vaccine." She agreed that adding "vaccine" might 

now have introduced some point of confusion and agreed to do some further editing. 

 

Dr. Treanor asked about confidence that the current system in place would effectively detect 

failures of this strategy and whether it was working as well as desired. Dr. Bell replied that 

hepatitis A is a reportable condition in all jurisdictions in the country, so all the health 

departments collect this information. There is now also enhanced surveillance in six or seven 

jurisdictions, so it’s likely that such an assessment could be made. 

Dr. Neuzil pointed out another potential source of confusion - the statement that vaccine in 

persons younger than two has not been studied. The most common group will be children 12 

to 23 months of age because that's where vaccine is routinely recommended, and yet some of 

them may not have received it yet when they've been exposed. She recommended that there 

be a line in the recommendation specifically for that group, saying children 12 to 23 months 

of age should receive the recommended hepatitis A vaccine. In addition, Dr. Neuzil felt the 

group should decide whether to say "also immunoglobulin" or not, with a special decision for 

the 12-to-23 month age group because they're targeted for universal vaccination, but they fall 

in between the two age groups in the recommendation. 

 

Dr. Bell said the trial in Italy, which did not have IG as a comparison group but did use 

vaccine at the licensed pre-exposure dosage, went down to age one. She did not know how 

many children aged one to two there were in that trial. However, the sentence is not exactly 

correct if one includes the results from the earlier Italian trial. That could make a difference, 

or the committee might prefer an additional, explicit sentence about children 12 to 23 months. 

Dr. Abramson thought just saying that “the post-exposure efficacy of hepatitis A in persons 

greater than 40, and persons with medical conditions has not been studied” covers the 

essence. Further details can go into the text. He asked if the committee wanted to have “less 

than two” in there, since it was already not recommending it to children less than one. Dr. 

Neuzil preferred to either take out “less than two” or add another sentence because, 

otherwise, there are two different age groups in the same paragraph and Dr. Abramson agreed. 

Dr. Susan Lett said she thought that the previous day the group had suggested that 

immunocompromised people and perhaps older people with liver disease should get IG and 

vaccine, but this was not reflected in the new wording. Dr. Bell responded that 

immunocompromised people don't respond as well to the vaccine, but there's no 

recommendation explicitly for pre-exposure vaccination of all immunocompromised people. 

They don't necessarily have worse hepatitis A outcomes, so the recommended groups for preexposure prophylaxis include chronic liver disease patients but not all immunocompromised 

people. 

Dr. Morse said he was uncomfortable with the last sentence because of questions about people 

less than age two and greater than 40. He felt it would be useful to see more of the Canadian 

data, then either remove the “two” or say “immunoglobulin can be used for children less than 

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58

two”. As for people over age 40, he noted that the U.K. recommends using immunoglobulin 

for people age 50 and above, and thought it would be useful to see the data they used to 

substantiate that recommendation. He noted that the average of age of participants who got 

either vaccine or immunoglobulin in Kazakhstan was around 12. He wondered how many 

study participants were actually over age 20 or 30, in order to give any useful information. 

Also, there were higher ALTs, a measure of liver function, in the vaccine recipients than those 

that received immunoglobulin. The U.S. has a much older population that’s not immune, and 

this might create problems. 

 

Dr. Baylor was uncomfortable with the definitiveness of some of the wording. Instead of 

saying “unvaccinated persons who recently have been exposed to HAV should receive a single 

dose of hepatitis A vaccine or IG,” he preferred "should receive IG" and then, "based on the 

limited data can receive hepatitis A vaccine." Such flexibility is more acceptable since the 

data do not support that indication for the label. The recommendation is using IG, but 

hepatitis A vaccine may be used based on the limited data. 

 

Dr. Greg Wallace reminded the group that if this was an affirmative vote, there would be a 

VFC vote, so it was important to sort out the language before the vote. He suggested using 

the following wording regarding efficacy: “The efficacy for post-exposure prophylaxis of IG 

or vaccine, et cetera.” That qualifier makes it clear that the committee is talking about 

vaccine efficacy for post-prophylaxis. 

 

Dr. Ciro Sumaya worried that by having the sentence that says: “Persons administered IG, for 

whom hepatitis A vaccine is also recommended, should receive a dose of vaccine 

simultaneously with IG.” in the second paragraph, it could be misinterpreted. He suggested 

putting that sentence in a separate paragraph, disengaging it from the sentence that precedes it 

now. 

 

Dr. Hull commented that the recommendation should explicitly state that people who have 

gotten one dose of hepatitis A should be vaccinated with a second dose. 

Dr. Treanor asked for clarification on what the committee was actually recommending: A)

“Vaccine and IG are completely equivalent and you can give whatever you want, depending 

on what's better for you”; B) “IG is what you should probably give most of the time, but if it's 

not around or, for some reason, you'd rather give vaccine, that's okay”; or C) “We really think 

you should mostly use vaccine, but you could use IG if you want to.” Dr. Abramson agreed 

that further editing for clarification was needed and asked the committee members if they 

were ready to vote or if they wanted to see more data first. 

Dr. Lieu said there would probably not be more data between now and June, but that more 

clarification was still needed as to whether the committee is saying that vaccine and IG are 

equivalent, or that there's a preference for one or the other. Dr. Abramson asked whether the 

committee needed more data before making a decision. Dr. Allos reiterated that there would 

be no more data, perhaps for years, and that the data presented the previous day would be 

published in a peer-reviewed journal. 

 

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59

Dr. Morse felt it might be worth re-examining the currently available data to see how many 

study participants were over age 20 and 30, and whether the numbers were large enough to 

reach any conclusions. There might be age-related details in the U.K. and Canadian data. 

Dr. Gilsdorf said that what was missing was an analysis by the working group about which of 

the three options Dr. Treanor mentioned was preferred. It would help to have the pros and 

cons of each one presented very clearly. The consensus was to put off the vote until June. 

DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS

ADSORBED, INACTIVATED POLIOVIRUS AND HAEMOPHILUS INFLUENZAE b 

CONJUGATE (TETANUS TOXOID CONJUGATE) VACCINE COMBINED

(PENTACEL) 

Dr. Patricia Joyce, National Center for Immunization and Respiratory Diseases

Pentacel, a combination vaccine being developed by sanofi pasteur, is a five-component 

vaccine, comprising DTaP-IPV-Hib. It has been used in Canada exclusively since 1997 in 

their childhood vaccination schedule. Pentacel is almost identical to Diphtheria, Tetanus, 

Five Component Acellular Pertussis, Inactivated Poliovirus and Haemophilus influenzae Type 

b Conjugate Vaccine (Adsorbed) (Pediacel®), which has been used in Europe. Pentacel and 

Pediacel differ in the force of the polio component. In Pentacel, the poliovirus is grown in 

human diploid cells, whereas in Pediacel, it is grown in vero cells. Sanofi pasteur has 

submitted a Biological License Application to the FDA for use of Pentacel as a four-dose, 

primary series in children at 2, 4, 6, and 15 to 18 months. 

Dr. Joyce showed a slide demonstrating the components of various DTaP vaccines. Pentacel 

is based on the sanofi pasteur product Diphtheria and Tetanus Toxoids and Acellular Pertussis 

Vaccine Adsorbed (Daptacel®), combined with PRP-T and poliovirus vaccines. However, in 

Pentacel, the pertussis components are slightly different from those in Daptacel. Pentacel 

contains twice the amount of pertussis toxin and four times the amount of FHA. The 

diphtheria component is equivalent to that contained in Daptacel. The Hib component is 

identical to ActHIB. The tetanus component is similar to Daptacel plus an additional amount, 

conjugated to PRP. Pentacel is administered intramuscularly in a 0.5 ml volume. Liquid 

DTaP-IPV, also known as Quadracel vaccine, is used as a diluent for lyophilized ActHIB. 

Pentacel is thimerosal-free. 

Pentacel was contrasted to other DTaP combination vaccines, such as Combination Acellular 

DTP and Hib Conjugate Vaccine (TriHIBit®), which is licensed only for the fourth dose of 

the DTaP and Hib series, and Diphtheria and Tetanus Toxoids and Acellular Pertussis 

Vaccine Adsorbed, Hepatitis B (recombinant) and Inactivated Poliovirus Vaccine Combined 

(Pediarix®), which was licensed by the FDA in 2002 and recommended by the ACIP in 

February 2003. Pediarix is licensed for three doses only at 2, 4 and 6 months, and is not 

approved for booster doses. 

If Pentacel receives FDA approval for the requested schedule of 2, 4, 6, and 15 to 18 months, 

the vaccine would fit into the childhood immunization schedule as follows: Pentacel doses 

given at 2 and 4 months would provide doses one and two of the primary series for DTaP, 

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60

poliovirus, and Haemophilus B. The third dose, given at 6 months, would provide the third 

dose of the series. A dose given at 15 to 18 months will provide the fourth dose of DTaP and 

Hib and an extra, or fourth dose, of IPV. 

If the FDA licenses Pentacel for use in the United States, the vaccine will be presented for 

consideration by the ACIP. In preparation for that review, the following measures are 

proposed to examine pertinent issues related to Pentacel and other combination vaccines: 

form an ACIP combination vaccine working group; review data on immunogenicity and 

safety; and consider the need to update the combination vaccine statement in the MMWR. 

 

Dr. Susan Lett asked Dr. Joyce to describe the antigens in the DTaP vaccines and the 

lyophilized part of the vaccine. Dr. Joyce responded that the vaccine, as it is being 

manufactured in Canada, consists of two vials, one of which is a 0.5 amount of liquid DTaPIPV. This is equivalent to Quadracel, which is not licensed in the US. Liquid DTaP-IPV is 

drawn from one vial and mixed with lyophilized Haemophilus b Conjugate Vaccine (Tetanus 

Toxoid Conjugate), (ActHIB®) in a second vial, then drawn back into a syringe, ready to 

inject. Pentacel has no hepatitis B component, whereas the combination vaccine Pediarix 

does. 

 

IMMUNIZATION SAFETY OFFICE STUDY AND SURVEILLANCE UPDATES

Dr. Robert Davis, CDC/ISO

Dr. Davis’s first presentation was an update on Guillain Barré Syndrome (GBS) among 

recipients of meningococcal conjugate vaccine (MCV4; trade name Menactra), covering the 

period from October 2006 to January of 2007. He presented data from the Vaccine Adverse 

Event Reporting System (VAERS) and from the Vaccine Safety Datalink (VSD), showing the 

observed compared to the expected rate calculations and age and season-stratified analyses, 

followed by a discussion on limitations of the data. 

GBS is a rapidly evolving polyradiculoneuropathy that generally manifests as a symmetric 

motor paralysis. This was reported on previously in the MMWR, where cases of GBS 

following receipt of MCV4 were reviewed. In October 2005, five cases were originally 

reported to VAERS. In April 2006, there were three additional cases reported to VAERS and 

published in the MMWR and in October 2006, nine additional cases of GBS were reported. 

Dr. Davis discussed two new cases through January of 2007, making a total of 19 cases that 

have occurred less than 6 weeks after MCV4 receipt as reported to VAERS. Four confirmed 

cases of GBS have also been reported in 13- to 19-year-olds, but those have an onset interval 

greater than 6 weeks following receipt of vaccination so were not included in discussion or 

analysis. Of the 19 cases of GBS following administration of MCV4 with an onset interval of 

2 to 33 days, 17 occurred in children 11 to 19 years old. Information from managed-care 

organizations within the VSD indicates that approximately 94 percent of MCV4 recipients 

were 11- to 19-years old. 

Dr. Davis then presented information on the number of GBS reports to VAERS within 6 

weeks of MCV4 administration by age at onset. There was one case among 11-year-olds, two 

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61

cases among 15-year-olds, two cases among 16-year-olds, three cases among 17-year-olds, 

seven cases among 18-year-olds, and two cases among 19-year-olds. 

The VSD Rapid Cycle Project from April 2006 through January 2007 indicates that 156,542 

doses of MCV4 have been administered and no cases of GBS have been observed among 

those recipients who were 11 to 19 years old. The expected number of cases was zero to one, 

based on the background incidence rate of GBS in this population. 

In the VAERS Observed, 1.78 cases per million person-months have been observed. HCUP 

data show 1.57 expected cases per million person-months and VSD data show 1.59 expected 

cases per million person-months. If these data represent the true magnitude of increased risk 

after vaccination with MCV4, then there are 0.89 excess cases per million person-months, and 

there are 17 observed cases and 10.8 expected cases divided by 6.93 million doses, or close to 

one excess case per million doses of MCV4 administered. 

Among 11- to 14-year-olds in the VSD, the rate ratio is 0.25, with confidence intervals 

ranging from 0.1 to 0.2. Among 15- to 19-year-olds, the rate ratio is 2.48, with confidence 

intervals from 1.30 to 4.55. So the risk for GBS after MCV4 is, in fact, greater among 15- to 

19-year-olds compared to 11- to 14-year-olds. One reason for this difference might be that 

15- to 19-year-olds routinely receive their vaccinations at the end of the summer in 

preparation for school, while the 11- to 14-year-olds receive them throughout the year. In 

addition, there are frequently circulating infections associated with risk for GBS. Even 

though this has been controlled for this season, there may be residual confounding due to 

seasonality in this data.

In summary, for 11- to 19-year-olds, there is no statistically significant evidence of an 

increased risk of GBS after MCV4 vaccination, although there appears to be a small increased 

risk for GBS after MCV4 vaccination in the 15-to-19 age category. 

The inherent limitations of VAERS require that these findings be viewed with caution. 

Substantial uncertainty exists regarding the risk estimate using either the HCUP or VSD 

background incidence rate. However, the timing of neurologic symptoms within 1 to 5 weeks 

shown in previous presentations remains of concern. The completeness of GBS reporting to 

VAERS is unknown. Under-reporting of GBS after MCV4 vaccination would raise the risk 

estimates. However, there has been no surge in GBS reports to VAERS after any of the three 

prior MMWR publications, and this would be expected if underreporting were marked. Also, 

the VSD has limited ability to detect rare adverse events, so not finding any GBS in that 

population of 156,000 vaccinees does not offer substantial reassurance regarding MCV4 

safety in terms of risk for GBS. 

Harvard Pilgrim has begun a larger study to provide a more definitive assessment. Data 

regarding the risk for GBS following MCV4 is expected in approximately 2 years. This study 

period is necessary to accumulate the required number of cases to attain sufficient statistical 

power to answer this question. In addition, an ongoing evaluation of GBS following MCV4 

vaccination is being performed using the VSD Rapid Cycle Project. 

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62

Dr. Davis proceeded to present an update of the ongoing thimerosal-autism case-control 

study. High doses of methylmercury exposure cause a range of neurologic impairments. 

Low-dose methylmercury exposure can also lead to more subtle neuro-developmental deficits, 

as shown by Grandjean et al., 1998. Thimerosal contains approximately 49 percent 

ethylmercury. The previous ACIP recommended immunization schedule could have led to 

mercury exposure exceeding the EPA safety limits for methylmercury exposure. Since 2001, 

all U.S. licensed vaccines recommended for children 6 years of age and younger have been 

manufactured in thimerosal preservative-free formulations with the exception of some 

formulations of inactivated flu vaccine. 

Ecologic studies have found that autism rates have continued to increase even after thimerosal 

has been removed from vaccines, as shown by Madsen (2003), Stehr-Green (2003), and 

Fombonne (2006) in three different countries. The Autism Cohort Study by Hviid in 2003, 

with a population-based cohort of almost half a million children, showed no association 

between thimerosal and risk for autism. Verstraeten (2003), in a larger observational cohort 

study within the VSD, found no statistically significant association at any time in the analyses 

between thimerosal exposure and risk for autism. 

In 2004, the IOM published a statement that the evidence favors rejection of a causal 

relationship between thimerosal-containing vaccines and autism, and that many of the 

epidemiologic research recommendations of the committee's 2001 report on thimerosal and a 

range of neurological developmental disorders are either under way or have been completed. 

Thus available resources should be focused on causes of and treatments of autism. 

In terms of the protocol development for the current case-control study, Abt Associates 

successfully competed for a contract competition in 2002. Input was provided by CDC staff, 

principal investigators from the VSD participating managed-care organizations, and a panel of 

independent, external expert consultants. The final analysis plan was approved by each of 

these external expert consultants. The primary research question was whether there was an 

association between the diagnosis of autistic disorder and the level of mercury exposure from 

vaccines and immunoglobulins. The study follows a 3-to-1 matched case-control design. 

Mothers are recruited from three managed-care organizations within the VSD. Children's age 

is 5 to 11 years, with birthdates ranging from January 1994 to December 1999. All children 

received vaccines during the period when thimerosal-containing vaccines were used 

frequently and, hence, became a relevant study population from which to draw the casecontrol population. 

 A parent interview is being administered to both cases and controls and allows collection of 

extensive data on confounders such as family demographics, medical history, and other 

relevant data. A Social Communication Questionnaire is being administered only to controls 

as a screening tool. SCQ-positive control children are then excluded from the study and 

replaced with normal controls. The mercury exposure periods being examined include 

prenatal mercury exposure, mercury exposure at birth through 28 days of life, and mercury 

exposure at one through seven months of life. There will also be joint analyses combining 

these exposure periods in various manners. Clinical case assessment is being done through 

clinical interviews with the mother; the Autism Diagnostic Interview-Revised, otherwise 

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63

known as the ADI-R; and an interview designed to measure if the child is having regressive 

autism. The clinical assessment of case children is being done with the Autism Diagnostic 

Observational Schedule (ADOS). Measures of cognition include the Raven's Colored 

Progressives Matrices test and the Mullins Scales of Early Learning. 

 Regarding power calculations for autism spectrum disorder, a sample of 320 autistic spectrum 

disorder children and 960 matched controls will be obtained. For prenatal exposure, this will 

provide 80 percent power to detect an odds ratio of 1.8 for every 12.5 micrograms increase in 

mercury received by the children. For the birth to 28 days exposure, this will provide 80 

percent power to detect an odds ratio of 1.9 per 12.5 micrograms increase. And for the birth 

to seven months' exposure, this will provide 80 percent power to detect an odds ratio of 1.1 

per 12.5 micrograms increase. Currently there are a total of 233 children with confirmed 

autistic spectrum disorder. The target is an additional 27 children with autistic disorder and 

an additional 60 children with autistic spectrum disorder. Complete data collection is 

anticipated by July of 2007. 

 

Discussion

Ms. Stinchfield stated that she was looking forward to the day when all vaccines are 

thimerosal-free and wondered if some of the influenza vaccine manufacturers could comment 

on that possibility. Phil Hosbach, sanofi pasteur, replied that they currently do have an 

unpreserved formulation of influenza vaccine, in a pediatric dosage form of 0.25 ml as well as 

a 0.5 ml formulation. Current capacity is about 8 to 10 million doses, depending on demand. 

They have never entirely sold out of the 0.25 ml dosage, including this year, but plan on 

expanding their fill-and-finish capability to continue to increase the availability of that 

product. Their new facility will expand influenza vaccine capacity to about 100 million 

doses. By then, around 2009, they will probably be able to transfer everything to unpreserved 

vaccine. Dr. Michael Decker, sanofi pasteur, further explained that the limitation is not the 

ability to remove thimerosal. Unpreserved vaccine must be packaged in single-dose 

containers and no one in the industry had the manufacturing capacity for the single-dose 

containers when the thimerosal issue arose. It takes half a decade or more to bring the new 

manufacturing facilities on line. 

Dr. Rennels said that GSK is working toward bringing thimerosal-free vaccines to the market, 

both from the Canadian and the Dresden production plants; however, this will not be in time 

for the next influenza season. Dr. Marie Mazur reported that CSL Biotherapies was working 

hard to be in the [U.S.] market this fall. The Australian company had removed thimerosal in 

2003 and most of their capacity has been converted to making a thimerosal-free product for 

the U.S. adult population. They are building additional capacity for 20 million doses of 

thimerosal-free product by 2010. 

Mr. Beck asked about the current availability of thimerosal-free vaccine dosages today as a 

substitute for receiving a thimerosal-containing vaccine. Mr. Hosbach replied that his 

company was able to manufacture and sell sufficient quantities. The issue was whether the 

doctors are stocking them. They have not yet sold out of thimersal-free vaccine. Dr. Baker

agreed that whether or not a child gets thimerosol-free vaccine often depends on whether the 

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64

site has it or not. 

Dr. Sam Katz asked whether the children in the study were being evaluated clinically only, or 

were their serum specimens or other specimens being obtained for eventual genomic analysis

or other testing. Dr. Davis replied that they were not obtaining biologic specimens from 

either cases or controls. However, if someone were to submit a proposal to do, for example, a 

gene-interaction analysis, they would be willing to contact patients and see if they would be 

amenable to providing swab smears for future analysis. 

 

Dr. Jane Quinn said that GSK had recently announced the FDA approval of formulation 

changes that remove residual thimerosal from their hepatitis B-containing vaccines, which 

include Hepatitis B Vaccine (Recombinant), (Engerix-B®), Pediarix, and Hepatitis A 

Inactivated and Hepatitis B (Recomninant) Vaccine (Twinrix®). These products will be in 

inventory with new NDC codes over the course of this year. 

 

Dr. Bill Schaffner asked whether the fact that the study was not obtaining any biological 

specimens implies that they are also not measuring mercury in its various forms in both the 

cases and the controls. In addition he asked for clarification of the role of the Social 

Communication Questionnaire in the study design. Dr. Davis replied that with the change in 

birthdates, it was felt that trying to obtain current mercury levels in biologic specimens of

either the mother or the child would actually add more “noise” for the amount of data that 

could be utilized in the study design. In addition, they were concerned about the possibility of 

having more trouble obtaining the required number of study participants if they had to donate 

blood or other specimens. Regarding the SCQ, this is a way to screen a general population for 

evidence of communication disorders that have been linked to an increased risk of being 

diagnosed as autistic spectrum disorder. 

 

Dr. Paul Offit, Children's Hospital of Philadelphia, wondered whether the study results would 

be available for the omnibus autism proceedings scheduled to be heard in mid June of this 

year. Dr. Davis felt this was highly unlikely. If data collection is completed in July of 2007, 

data analysis would take anywhere from 12 and 18 months, and writing, clearance, 

submission to a journal, acceptance, and publication would probably take another 6 to 12 

months. Study authors would not want to release the data before peer review. However, the 

thimerosal and the neurodevelopmental study has been completed, written, gone through 

clearance, and is being submitted to a peer-reviewed journal. Autism is not part of that study. 

It looks at neuro-developmental outcomes among population-normal children with varying 

rates of exposure to thimerosal in these same time periods.

Next, Dr. Iskander presented safety updates on two recently licensed, adolescent and adult 

acellular pertussis vaccines, in addition to safety data on the newly licensed herpes zoster 

vaccine. Data sources included VAERS, VSD, and an evaluation of the use of TDaP during 

mass vaccination of healthcare personnel in an outbreak setting. VAERS, a spontaneous 

reporting system for vaccine adverse events, is well suited for preliminary safety evaluation of 

new vaccines. It is subject to well-defined limitations common to other passive surveillance 

systems. VAERS has recently upgraded its adverse event coding system to conform with 

international standards. The VSD network serves as the primary U.S. safety system for 

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65

testing vaccine-safety hypotheses that emerge from VAERS or other sources. Rapid Cycle 

Analysis allows timely surveillance of new vaccines, but the network's size may limit rare 

event detection and study - specifically, events with an incidence of 1 in 10,000 vaccinees or 

rarer. 

Through the end of January 2007, VAERS had received a total of 1,379 domestic adverse 

event reports for licensed TDaP products. Two-thirds of reports involved females and just 

under half involved adolescents 11 to 18 years of age. Eighty percent of the reports involved 

the sanofi pasteur product Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular 

Pertussis Vaccine, Adsorbed (Adacel®). This, most likely, reflects differences in market 

distribution between that product and the GlaxoSmithKline product product Tetanus Toxoid, 

Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Boostrix®). 

Approximately two-thirds of reports have involved adverse events with onset within 24 hours 

of vaccination. Just over half have been reported by healthcare providers. Nearly 90 percent 

had recovered from the event at the time of the report. Consistent with pre-licensure data, 

most are systemic complaints, such as fever, pain, and headache, along with injection-site 

reactions. Five percent of reports met regulatory criteria for seriousness. Most of these 

involved hospitalization. The regulatory definition does not require any determination of 

causal relationship to vaccination. The breakdown between the two licensed products, among 

serious events, is similar to the overall adverse event breakdown. Two of the three reported 

deaths involved adults who died from complications of underlying cardiac disease. The third 

case, which has been presented to the ACIP previously, involved an adolescent male who died 

of a previously undiagnosed cardiac arrhythmia two weeks following vaccination. 

Among eight reports of Guillain Barré Syndrome following TDaP, half occurred at very brief 

intervals following vaccination and half involved at least one co-administered vaccine. All 

reported case-patients are in various stages of recovery. A variety of vaccine mix-ups 

involving TDaP have been reported. Other vaccines involved have included pediatric DTaP 

as well as Pediarix. Among these reports, no serious clinical outcomes were reported. 

Additional safety data on TDaP was collected following a suspected pertussis outbreak in 

which healthcare providers at a major medical center were offered the vaccine. More than 

4500 were vaccinated. Vaccinees were surveyed for solicited and unsolicited adverse events 

as well as medically attended events after two weeks. Serious adverse events, as defined in 

federal regulations and in VAERS, were monitored for a two-month period. The overall 

survey response rate approached 60 percent. Respondents did not differ demographically 

from the group of vaccinees as a whole. Rates of solicited local and systemic adverse events 

ranged between 7 and 18 percent. Rates of solicited adverse events did not differ significantly 

between persons who had received Td or TT in the previous two years compared to longer 

intervals from a prior vaccination. 

In summary, most adverse events reported following TDaP were non-serious and had a close 

temporal relationship to vaccination. Deaths were not consistent with a causal relationship to 

vaccine, and GBS reports were not clustered by plausible onset interval or single vaccine 

exposure. Among healthcare providers receiving the vaccine who were actively followed up, 

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66

there was no increased risk of local or systemic reactions compared to pre-licensure data, even 

among those vaccinated more recently with Td or TT vaccines. 

Next, Dr. Iskander reviewed emerging safety data regarding zoster vaccine. The total number 

of VAERS reports received through mid January, along with the net dose distribution through 

January, was shown. The number of serious adverse events reported to date is less than ten, 

and no post-vaccination deaths have been reported. The median age of persons involved in 

VAERS reports for zoster vaccine is 65, with a 3-to-1 female-to-male ratio. The median 

symptom onset interval following vaccination is one day. 

 The most commonly reported adverse events were injection site reactions. Rashes are both 

zosteriform and nonzosteriform types and systemic reactions included pruritus and fever. 

Rashes described as being zoster and nonzoster-like did not differ in terms of onset interval or 

patient demographics. VAERS does not routinely receive photos of rashes involved in 

adverse events, so these are based on textual symptoms descriptions contained in the regional 

reports. Medical errors involving zoster vaccine have occurred among both adults and 

children. Vaccines involved in the mix-up have included varicella vaccine and Measles, 

Mumps, Rubella and Varicella Live Vaccine (ProQuad®), as has been the case with a TDaP. 

No serious outcomes have been reported. 

Within the Vaccine Safety Datalink, safety surveillance is being conducted in two age strata 

of potential vaccinees. Among 50- to 59-year-olds, with the possible anticipation that there 

may be some off-label use, a cohort of 563,175 persons will be under surveillance. Among 

persons 60 years of age and older, just over 660,000 persons will be under surveillance. This 

conforms to the FDA license and ACIP recommendations for use of this vaccine. The 

specific sites and populations were shown. 

Adverse events selected for active surveillance include events judged to be plausible 

following Zoster Vaccine, Live (Zostavax®) or related vaccines, events that have been 

commonly reported to VAERS, and chronic underlying medical conditions of importance in 

those greater than or equal to 60 years of age. Events falling among the previously listed 

categories were noted. Unlike in VAERS, rates of these events will be compared between 

vaccinated and unvaccinated cohorts. Analyses will be adjusted to account for confounding 

of vaccination status by underlying disease status. 

 

In summary, to date, VAERS safety data for zoster vaccine is consistent with pre-licensure 

data and events anticipated on the basis of knowledge of the vaccine product and the target 

population for vaccination. The vast majority of reported events have been non-serious and 

demonstrate close temporal proximity to vaccination. Preventable vaccine administration 

errors have been reported. Active surveillance for selected adverse events among the cohort 

of over one million people is proceeding within the VSD. 

Discussion:

 

Mr. Beck asked what the comparable number of vaccinations would be for the 1,379 reported 

cases. Drug manufacturer representatives indicated they did not have that specific 

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67

information at hand. 

Dr. Baker asked about the period of time for which reports on adverse events for zoster 

vaccine would be taken. Some of these events could occur much later and theoretically be 

biologically related. Dr. Iskander replied that they do not routinely exclude from the initial 

analysis any event regardless of its onset interval. They do present data in terms of median 

days to onset, but there are no time limitations either on reporting or on analysis. 

 

Dr. Baker’s second question was about TDaP and the more than 4000 people who were 

vaccinated during the outbreak. She noted that one of the barriers to getting recommended 

groups vaccinated with TDaP is this limitation of a prior TT or Td, and these are very 

reassuring data. She wondered about loosening the limitation because currently, for example, 

a 13-year-old who received TT one year previously because he had stitches in his head could 

not be protected against pertussis, due to the two-year cutoff limitation and the five years that 

FDA thinks is most desirable. Dr. Iskander replied that the current wording suggests that 

intervals as short as 18 months are permissible and there may be permissive wording allowing 

even shorter intervals. Dr. Decker further explained that the current recommendation contains 

enough “wiggle room” so that anyone be vaccinated. He referred to a study of about 8,000 

people in Prince Edward Island, where the vaccination intervals between prior Td and 

subsequent Adacel were as short as 18 months, and which found no relationship between local 

adverse events and the timing of prior Td. The only relationship, a “soft” one, was with the 

number of prior AP doses and had nothing to do with the Td. Dr. Wallace added that both 

his branch and the safety division receive distribution data on an annual basis. The 

unanswered question is really the gap between the number of doses distributed and how many 

were actually administered. It is not useful to break that data down on less than an annual 

basis, especially with new vaccines where the pipeline is still being filled, as has been 

demonstrated by some of the analysis of the rotavirus vaccine and MCV4. 

 

Dr. Karen Broder agreed that the data about intervals were very reassuring. In the healthcare 

worker population, the rates of the selected local adverse events and subjective fever were not 

higher in the healthcare workers who reported receiving Td or TT less than two years earlier 

than in the healthcare workers who had a longer interval. Those data are consistent with the 

permissive recommendation to use TDaP in populations less than two years. Dr. Abramson 

asked about the percentage of hospitals that are implementing the TDaP. Dr. Broder 

promised to email that information or have it available for the June meeting. 

Dr. Ciro Sumaya asked how the administration errors with zoster vaccine compared with 

other vaccines. Dr. Iskander replied that, based on anecdotal and unpublished data, despite an 

increase in alerts on consumer safety websites, more errors with this vaccine are not being 

seen. With more vaccines being licensed, especially vaccines with similar contents (varicella 

vaccine, a zoster vaccine, and an MMR-varicella vaccine), and new types of medical practices 

taking on vaccination, this may just be part of a general trend. Fortunately, most of these 

errors do not result in adverse clinical outcomes, but it certainly warrants further attention. 

There are some data in the process of being submitted for publication involving tetanus toxoid 

vaccine and PPD mix-ups, along with other kinds of mix-ups. 

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68

Dr. Baker returned to the interval issue and pointed out that the language says to wait 2 years, 

which is a barrier for post-partum women and health care workers, for example. She 

recommended that the committee reconsider the 2-year restriction. 

Dr. Nancy Messonnier, NCIRD, said the general impression was that uptake of vaccine in 

healthcare workers was low because the recommendations were just published. In the several 

pertussis-like illness outbreaks investigated this year in hospitals, use of the vaccine before 

those events has been low. The data were not in, but she thought a plateau had not yet been 

reached. 

 

Dr. Harry Keyserling wondered if the vaccine manufacturers or the FDA had considered

making similar antigen-containing vials look different, which would certainly contribute to 

fewer errors. Dr. Adrian Dana reported that Merck had been looking at errors and mix-ups in 

vaccine, specifically the Zostavax and Varicella Virus Vaccine Live (Varivax®) vials. After 

calling practitioners, it appears that mix-ups occur because vaccines are kept in the freezer 

and whoever takes them out doesn’t look carefully or isn’t aware there are different vaccines. 

Merck tried, when licensing Zostavax, to be sure that the generic name contained the word 

"zoster" first and not "varicella." 

Dr. Abramson asked whether there were any official recommendations on the Merck web site 

about what should be done if the varicella vaccine is mistakenly given instead of the zoster, or 

vice versa. Dr Dana replied that manufacturers really were not in a position to give official 

medical guidance. It would depend in which way the mistake went – if the person received an 

inadequate dose or a higher dose than what was intended. 

Dr. Mark Feinberg informed the group that planning had been launched for a study to address 

some of these issues, specifically looking at total diphtheria content received by adolescents 

and adults, timing of the receipt of those varying content levels and rates of both local and 

systemic reactions. 

Dr. Iskander noted that this discussion belongs under patient-safety, which focuses on rootcause analysis. Follow-ups of VAERS reports can be done, but the simple question of why 

errors happen can trigger a very complex, root-cause type of analysis. 

 

Dr. Wallace pointed out that when people are looking for guidance for errors, including coldchain errors, they usually end up going to the grantees and then eventually CDC must struggle 

to give guidance with limited data and information. It would be very helpful if manufacturers 

could provide more information so that better advice can be provided. 

 

Dr. Jeff Duchin, NACCHO, addressed the complications at the clinical practice level with the 

increasing number of vaccines and the complexity of the schedule. Currently the VFC 

program provides funding for site visits to practitioners who administer VFC vaccine. These 

site visits focus on vaccine-safety issues, administration errors, and quality of clinical practice 

to improve the quality of practice and decrease errors. A similar mechanism is needed for 

adult vaccines, which would allow qualified public health professionals to be brought into the 

community to do this type of training. 

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69

HUMAN PAPILLOMAVIRUS VACCINE

Dr. Janet Gilsdorf, ACIP, HPV Vaccine Workgroup Chair

Dr. Gilsdorf updated the committee on some of the group’s activities, which include 

reviewing data from clinical trials, reviewing new epidemiological data on HPV infection, 

and considering additional modeling and cost-effectiveness analyses. GSK has announced that 

they plan to file for FDA approval in April of 2007. In anticipation of possible licensure of 

that vaccine, the workgroup will develop recommendation options for use of the bivalent 

HPV 16/18 vaccine for ACIP consideration. It will also update the ACIP statement to include 

bivalent HPV vaccine when it is licensed. The working group plans to review the bivalent 

HPV vaccine Phase III data in June 2007 and present options for bivalent HPV vaccine 

recommendations in October 2007. 

Quadrivalent HPV Vaccine – Gardasil 

Dr. Eliav Barr, Head of HPV Vaccine Programs, Merck Research Labs

Dr. Barr presented an update of efficacy findings in the clinical program for Gardasil. There 

are four efficacy studies: one that involved an HPV-16 vaccine prototype with efficacy 

through four years, and three studies of Gardasil, the quadrivalent vaccine with follow up 

through an average of 2.8 years (two Phase III studies) and 5 years (one Phase II study). 

The presentation focused on updated analyses of the efficacy and population impact of 

Gardasil, including one further year of follow-up in the Phase III efficacy studies relative to 

the data set presented to ACIP last year. Other studies are ongoing. As Scandinavian subjects 

end their participation in the Phase III trials, they will be enrolled in a long-term effectiveness 

follow-up program. Towards the end of this year, it is anticipated that results for a study in 

mid-adult age, which examines the efficacy of Gardasil in 24- to 45-year-old women, will 

become available. Such women have continuing risk of development of HPV infection 

disease and precancerous lesions. Like all vaccines, HPV vaccines have a lower immunity by 

age at which the first dose is given. Merck felt it was more prudent to make claims about 

efficacy in adult women using efficacy data rather than relying on extrapolations from 

immunogenicity, particularly since the minimum protective anti-HPV level has not been 

demonstrated. 

Merck has ongoing studies in men looking at both genital disease and infection and anal 

disease. Studies of Gardasil are being conducted or are in the planning phase in various 

immunocompromised populations, including solid organ, bone-marrow transplant and bonemarrow transplant patients and HIV-positive patients. A large program to encourage and 

manage uptake in the developing world is being conducted in collaboration with PATH, a 

nongovernmental organization. 

Dr. Barr then focused on the results of the updated efficacy analyses for Gardasil. The Phase 

III trials had been analyzed using pre-specified target endpoints, and the first set of these were 

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70

used to conduct the analyses that served as the basis for licensure. But the studies continued 

for an additional year and are still on-going. 

There was another pre-specified milestone for analysis, relating to an evaluation of the impact 

on the overall rates of CIN 2/3 or AIS (caused by vaccine or non-vaccine HPV types). The 

trigger for this analysis was met in summer 2006. The results now represent about a year of 

follow up above and beyond the follow-up included in the original analyses. The main 

analysis population is women who were naïve to the relevant HPV types at enrollment, 

remained free of infection with the relevant types through one month post completion of the 

vaccination regimen, and who received 3 doses of vaccine/placebo within a one-year time 

frame. Dr. Barr focused mostly on the overall impact of CIN 2/3 and adenocarcinoma in situ, 

as well as other endpoints, regardless of the causal HPV type, in two populations. 

Dr. Barr showed the database submitted for licensure in 2005 and the updated results. 

Subtracting out the numbers for each endpoint reveals that, in the intervening period, 35 cases 

of CIN 2/3 caused by HPV 16 and 18 developed, of which 34 occurred in the placebo group 

and one in the vaccine group. The last case is unusual and may reflect contamination. With 

respect to vulvar and vaginal pre-cancers, efficacy remained high. 

A single case of HPV 16-related CIN 3 in the group that received Gardasil was described. 

This analysis had the benefit of testing for common non-vaccine HPV types, which revealed 

that this woman had been infected with HPV 52 at baseline, remained infected for the next 

three years, and had an abnormal Pap test at Month 32-1/2 that led to a biopsy. The biopsy 

showed CIN 3. It was positive for both 52 and 16. This was the first detection of HPV 16. 

The next month, the patient underwent definitive therapy because she had a CIN-3 lesion. A 

biopsy was taken at that time, and a LEEP specimen was divided into four pieces, as per the 

study protocol. All of these lesions were typed, and all were positive for HPV 52 but not for 

HPV 16. 

No cases with similar patterns were observed in placebo subjects in Protocol 015, the study in 

which this case was seen; that is, a situation where a case is called an endpoint case, the 

subject is positive for a vaccine and a non-vaccine HPV type, and the only time that there is 

detection of the vaccine type is on a single biopsy. There is reason to suspect that the case 

may represent contamination, however, it meets endpoint definition and is reported as a case 

in the group that received Gardasil. This subject was not tested for anti-HPV levels because 

the subject was not in the consistency lot sub-study of this protocol. 

Analyses were conducted to evaluate the efficacy of Gardasil with respect to HPV 6/11/16/18-

related cervical, vulvar, and vaginal disease, the broad spectrum of disease, including lowgrade abnormalities. Efficacy remained high. In the period since the closing of the last 

analysis data set, another two cases were observed in the group that received Gardasil, 

including the one case described above, plus 65 cases in the placebo group. So the efficacy 

actually went up slightly, and the 95 percent confidence interval is tightened. The same is 

true with vulvar and vaginal lesions, including genital warts. 

A similar pattern is seen with the new cases. As is the case with the HPV 16-related CIN 3 

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71

lesion described previously (and included here as well), the second additional case of CIN 

was a woman who was chronically HPV-56 infected at baseline, had remained infected, and 

had HPV-56 infection in every CIN 1 lesion found; in one LEEP specimen, she was HPV-18 

positive. These cases may point out limitations of using highly-sensitive HPV typing for 

definitive determination of causality. But overall, the vaccine's efficacy was high and 

remained so. The results through three years of follow up are exactly as expected, given that 

the high efficacy of Gardasil has been demonstrated through Year 5 of follow up. The data 

presented represent a much larger data set that confirms those Phase II results. 

Dr. Barr then talked about the impact in the general population. The clinical trials enrolled 

women regardless of baseline HPV status. Because Gardasil is a prophylactic vaccine, the 

primary analyses were conducted in women who were naïve to the relevant HPV types 

(prophylactic efficacy). However, it was also of interest to evaluate the impact of the vaccine 

among the general population of women regardless of the baseline HPV status. The 

enrollment of the clinical trials program for Gardasil did not exclude women who were 

infected with HPV at baseline, and thus there was a substantial amount of infection at 

baseline, which obviously impacted the population-impact findings. 

The results for HPV 16/18-related cervical cancer, vulvar cancer, and vaginal cancer efficacy, 

using surrogates, which include HPV-infected women at baseline, show that the efficacy or 

percent reduction, particularly for CIN, has improved between the original analysis database 

and the current database that includes an additional year of follow-up. In the intervening time 

period, 20 cases were observed among subjects who received Gardasil, as opposed to 50-54 

cases in the placebo group. All of the cases in the group that received Gardasil were due to 

prevalent HPV infection. In the placebo group, only 14 were due to prevalent infection, and 

the rest were due to incident infection. Thus the benefit of the vaccine becomes more 

apparent. With VIN 2/3 and VaIN 2/3, the efficacy is already high,. There is much less 

prevalent disease, as the time-to-event curves demonstrate. 

At the beginning of the follow up, the cumulative incidence is comparable, since all cases 

were due to infections present at baseline, which Gardasil and other prophylactic vaccines 

would not impact. However, after a period of time, the curves diverge and continue to do so. 

Women remain at risk for HPV 16/18-related CIN 2/3 and AIS, but there is a flattening of the 

curve in the group that received Gardasil. As these women are followed for longer periods of 

time, a broadening of the split and a better percent reduction will be seen. 

The same results are seen with the overall incidence of CIN caused by the four types as well 

as vulvar and vaginal lesions. There were 22 cases in the group that received Gardasil since 

the last time analyses were done and 97 in the placebo group, demonstrating the unmasking of 

the efficacy of the vaccine. For vulvar and vaginal lesions, there were four cases in the group 

that received Gardasil and 90 cases in the placebo group. The time-to-event curves have 

slightly different Y-axis scales: one 6 percent and one 5 percent. But the results are exactly 

the same as for CIN 2/3. The external genital lesions are pretty much flat and now there are 

very few cases. The same is true with CIN, and the curves continue to diverge over the 

course of time. Women continue to be at risk for developing these infections and diseases 

over this entire period of time, even well into their twenties. 

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72

 

Dr. Barr then turned to the overall incidence of disease regardless of the causal HPV types. 

The first population was one that was intended to be completely HPV naïve. Testing was 

conducted for 14 common HPV types to determine the status of subjects with respect to 

infection with common HPV types at vaccination onset. The relevance of this approach is that 

it approximates a population of HPV-naïve adolescents and young adults, in order to study the 

impact of the vaccine on purely incident disease. The population thus generated represents 

about half of the study population of young adult women. It is not a completely HPV-naïve 

population because testing for all high-risk HPV types was not conducted, but it was close. 

Analyses were also conducted in the general population. For the completely naïve population, 

administration of Gardasil resulted in a 46 percent reduction in the incidence of CIN 2/3 or 

AIS caused by vaccine or non-vaccine HPV types. Subjects with prevalent HPV infection 

certainly had a lot of disease, and when added up, a masking of the effect of Gardasil is seen. 

Nevertheless, there are statistically significant results for all endpoints. The numbers in the 

group that received Gardasil are always lower than those in the placebo group because women 

who are infected at baseline are at high risk for developing a second and third infection, and 

Gardasil prevents a large proportion of those infections. So even among infected women, 

there is a difference, and the benefit of the vaccine will become more apparent over time 

because the proportion of incident cases will become greater in the overall mix. 

The time-to-event curve in the completely naïve population shows a lag until disease becomes 

detected (subjects first have to acquire infection, then develop disease). There is still some 

prevalent disease because the study did not screen for all HPV types at enrollment. But then 

the curves separate and continue to do so over time. In the general population, there is such 

heavy burden of CIN 2/3 at baseline, so that the lines of separation are slower to diverge, but 

they do diverge over time. The reductions induced by the vaccine become more apparent and 

the difference is now statistically significant. 

Prevalent cases of external genital lesions are less common than prevalent cases of CIN 

because detection does not require screening – women detect the lesions and get treated. Also, 

subjects with a history of genital warts were excluded from enrollment. What is seen is a 

substantial separation of the curves early on, which demonstrates what happens when vaccine 

is given in a setting with somewhat lower prevalence. 

Cross-protection is a hot topic in this field and two analyses are being conducted to examine 

whether this vaccine will impact the incidence of infection and disease caused by types 

related to HPV 16/18. Early, preliminary results of the first analysis are quite encouraging, 

showing impact on a set of related HPV types. The effect is seen for cervical, vulvar, and 

vaginal disease. Analyses to confirm these results are still under way. 

 Another analysis is evaluating persistent infection, which is not a critical endpoint, per se, but 

it provides a good mechanistic evaluation that helps look at the disease without the need for a 

Pap test. Such an analysis would prevent ascertainment bias and other issues that affect the 

statistical analysis of cross-protection. Those results will be presented over the next few 

months. 

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73

 In conclusion, the new data show the continuing efficacy of the vaccine. The overall risk of 

cervical, vulvar, and vaginal cancer - using surrogate markers, the overall risk of CIN, the 

overall risk of external genital lesions, regardless of the causal HPV types - are reduced 

among the subjects who received Gardasil. And the benefit continues to improve over time. 

Other data shared with the work group show reductions in Pap test abnormalities and cervical 

procedures. The preliminary cross-protection data will be shared with the work group in the 

very near term. 

 

Discussion

 

Dr. Treanor asked whether it would be correct to say that the RMITT-2 population is a subset 

of the per-protocol population. After Dr. Barr confirmed this assumption, Dr. Treanor asked 

what proportion of the per-protocol population was in the RMITT-2 population. Dr. Barr 

replied that the per-protocol population is a one-type-at-a-time population. However, 

approximately 83 percent of the population participated in at least one per-protocol 

population: either the 6, the 11, the 16, or the 18; whereas, for the RMITT-2 population, about 

50 percent of the population participated in that analysis. It is not possible to just subtract one 

from the other to determine the protection against nonvaccine. However, one can subtract the 

completely HPV naïve population from the general population, which includes everyone in 

the study. 

Dr. Treanor asked whether there was a suggestion that the vaccine had an impact on the 

development of CIN in people who were already 16/18 positive at the beginning of the study. 

Dr. Barr replied that this was a real phenomenon to the extent that it prevents CIN caused by 

types other than those found at baseline. For example, a woman who is HPV-16 infected is at 

a much higher risk than the general population of women for developing 6/11/18 infection, 

either by her behavior or her partners, or by some intrinsic factor. The reductions represent a 

benefit with respect to the types for which she is negative. Dr. Treanor asked whether, for a 

person who is Type-18 positive at the beginning of the study, vaccination has no impact on 

the rate with which that person might subsequently develop CIN 18. Dr. Barr responded that 

the data do not show such a benefit. There is a benefit among women who have already 

cleared their infection and remain seropositive. Their rate of reacquisition of disease is lower, 

and the vaccine helps prevent that reacquisition. 

 

Dr. Morse asked whether the placebo group was offered the vaccine, given the overall benefit 

shown. Dr. Barr replied that the results were unblinded in November of last year and the 

placebo group is receiving vaccine now. 

 

Dr. Abramson asked if there was something more than just a passive system in the Phase IV 

that would provide information about this vaccine in pregnancy. Dr. Barr replied that there 

would be follow up in the clinical trials on all pregnancy outcomes. In addition, a postmarketing study, which is going to look at exposure in 44,000 women and children at an 

HMO in the U.S., will look carefully at pregnancy. In Scandinavia, which has extensive 

vaccination and pregnancy databases, there are plans to link vaccine allocation with 

pregnancy status and look at pregnancy outcomes in a comprehensive fashion. 

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74

 

Dr. Davis said that because this vaccine is being given to a population that may get pregnant 

and other vaccines for the same age group are coming along, a pregnancy cohort within the 

Vaccine Safety Datalink is being created so that all pregnancies within that population will be 

followed, and outcomes on the developing infant can also be assessed. 

 

Bivalent HPV Vaccine – GSK

Dr. Gary Dubin, Director, HPV Development Program, GlaxoSmithKline

Dr. Dubin gave an update on GSK’s recent clinical trial results and what is likely to come in 

the next few ACIP sessions. The vaccine that GSK has been developing for a number of 

years focuses on HPV 16 and 18 as targets for prevention, and consists of HPV 16/18 viruslike particles and the AS04 adjuvant, which has been included in the formulation because 

early clinical studies found that it enhanced immunogenicity compared to other formulations 

with aluminum-hydroxide adjuvant. 

HPV 16 and 18 is responsible for about 70 percent of cervical cancers globally, and is even a 

bit higher in the U.S. than in some of the other countries. GSK has designed its development 

program to focus on cervical cancer prevention in women, which is believed to be a costeffective strategy. Based on the modeling studies, high vaccine coverage levels will be 

required to ensure the best cervical cancer prevention in using the most cost-effective 

strategy. Clinical trials have been conducted in a broad age range, including girls and women 

between the ages of 10 and 55 years. One study specifically focused on women in the older 

age range.

Dr. Dubin presented some early Phase II immunogenicity data comparing two different 

formulations of vaccine - a formulation that contains the AS04 adjuvant, and a formulation 

that contains the same VLP dose formulated with aluminum hydroxide. This is actually two 

studies with a pooled analysis, which follow women out through four years from the 

administration of the first dose of vaccine. He then showed HPV-16 results and HPV-18 

results, as well as inhibition ELISAs, which measure surrogate neutralizing activity. Over the 

course of the four-year follow-up period, higher antibody responses were observed with the 

AS04 formulation compared to the alum-based formulation for both of the HPV types. 

 

GSK has also conducted some early studies looking at whether the adjuvant made a difference 

in induction of memory B-cells, and those data show that the formulation of vaccine with 

AS04 induces a higher frequency of memory B-cells. This is at peak responses, one month 

after the third dose, for both HPV 16 and 18, or compared to the alum-formulated vaccine. 

Based on the early development work, where the decision was made to formulate the vaccine 

with the AS04 adjuvant, the first efficacy study, initiated in 2001, was a double-blind, 

randomized control trial where about 1100 women 15- 25 years of age were enrolled and 

randomized to receive the active vaccine or control (aluminum hydroxide) on a zero, one, sixmonth schedule. Prior to enrollment, women were required to be naïve for a panel of highrisk HPV types. 

 

The first study (HP-001) evaluated vaccine safety, immunogenicity, and efficacy up to 27 

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75

months following administration of the first dose of vaccine. Women who completed the 

study were then offered the option of participating in a long-term follow-up study, referred to 

as HPV-007. This study is planned to continue to follow women for six and a half years after 

administration of the first dose of vaccine. Results from an interim analysis from the HPV007 study were published a year ago in the Lancet. This first interim analysis presented 

results following women through four and a half years of follow up. The second interim 

analysis extends the follow-up period and adds more statistical robustness because of events 

occurring over the additional year of follow up. The data presented by Dr. Dubin focused on 

the entire five and a half year follow-up period. A final analysis of this study with the full six 

and a half years of follow up will be available later this year. 

Dr. Dubin showed a slide illustrating the basic design of the original efficacy study, the HPV001 study, and then the follow up of Phase HPV-007. The follow-up phase is being 

conducted in a blinded fashion, so the study team conducting and responsible for the study 

has not been unmasked in terms of individual treatment-group assignments for subjects. The 

original study enrolled 1113 subjects who were randomized to receive vaccine or placebo. 

There was good balance between the two groups, and the women were followed for up to 27 

months. There were additional activities during the blinded, long-term extension phase of the 

study. GSK continues collecting blood samples for serology and cervical samples for HPV 

and DNA testing. If a woman has an abnormal cervical cytology, she is referred to 

colposcopy based on a management algorithm similar to what was used in the parent study. 

HPV 16 and 18 efficacy endpoints, which include virologic endpoints, were assessed. 

Incident infection was the primary endpoint of the original study. Efficacy against persistent 

infection was also assessed, using either a 6- or 12-month definition of persistence, abnormal 

cytology, and CIN lesions associated with the vaccine types. This study also provided an 

opportunity to do preliminary assessments of the ability of the vaccine to prevent incident 

infection with other oncogenic types that are important in cervical cancer. Types 45 and 41 

are the two most common types after HPV 16 and 18. 

Dr. Dubin showed HPV-16 immunogenicity data using a binding ELISA from the pool of five 

and a half years follow up. The peak responses are seen at Month 7, which is one month after 

the third dose of vaccine is given. At about the Month 18, the antibody titers begin to plateau, 

and both for HPV 16 and for HPV 18, and there appears to be a relatively stable plateau in the 

antibody titer through the last time point assessed for immunogenicity, which is 63 to 64 

months. In this analysis, antibody titers are fairly similar to what were seen in the earlier 

phases of follow up. The majority of subjects remain seropositive, even at the latest time 

points. At the last time point assessed in this analysis, the geometric mean antibody titer was 

still about 11-fold higher than titers associated with natural infection with HPV 16. The HPV18 results are almost identical to HPV 16. Again there is a relatively stable plateau of 

antibody titers throughout the entire follow-up period, with almost all subjects remaining 

seropositive through the later time points. 

Dr. Dubin summarized results from the combined analysis (HPV001/007) and the follow up 

study. The endpoints assessed include incident infection, 6- and 12-month persistent 

infection, and abnormal cytology and CIN lesions. For all endpoints associated with HPV 16 

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76

or 18, very high levels of efficacy are observed throughout the five and a half years of follow 

up. The results from the extended follow-up phase show no evidence of waning protection 

against any of these endpoints. 

Dr. Dubin then broke down data from the extended follow-up phase only, which is essentially 

Years 3 through 5-1/2, from the end of the HPV-001 study through the second interim 

analysis. For each of the five endpoints, a very high level of efficacy was observed with 

evidence of complete protection against the most biologically relevant endpoints: persistent 

infection, abnormal cytology, or CIN lesions. In the extended follow-up phase only, the 

number of CIN lesions is somewhat limited, although the pooled analysis increases the 

numbers a bit. Most of the confidence intervals around the efficacy estimate excluded zero, 

so the lower limits are relatively high for most of the endpoints. 

Dr. Dubin next focused on HPV 16/18-related CIN 2-plus and showed the initial results in the 

HP-001 study, where there were a very limited number of cases, and then a progression as 

cases of CIN 2-plus associated with vaccine types continue to accrue. The combined analysis 

now spans the five and a half year period, with additional cases of CIN 2-plus. The number 

of endpoints is still limited, as this is a Phase II study but the study provides good evidence of 

vaccine efficacy against very clinically relevant endpoints. The data will be supplemented 

with data from GSK’s large ongoing Phase III program. 

Results were presenting showing the overall efficacy of the vaccine on lesions, either 

cytology abnormalities that are graded ASCUS or worse, CIN 1 or worse lesions, and CIN 2 

or worse lesions when considering lesions independent of HPV-DNA status. These are 

cumulative data over the five-and-a-half-year period. Similar data were previously reported, 

but with increased numbers the results are more robust. The point estimate of vaccine 

efficacy for each of these endpoints is greater than what might be expected if estimating the 

proportion of cases caused by HPV 16 and 18 alone, based on available data from natural 

history studies. For CIN 2-plus, for example, the point estimate is about 67 percent, with an 

expectation that 50 percent of CIN 2-plus lesions would likely be caused by HPV 16 and 18. 

To further understand whether the vaccine is actually inducing protection against non-vaccine 

types that might be responsible for the observation of an effect broader than expected with 

HPV 16 and 18 alone, GSK conducted analyses to evaluate efficacy against virologic 

endpoints for other oncogenic types. Data were previously published through four and a half 

years showing efficacy against incident infection with HPV 45 and 31. These are the third 

and the fourth most common types globally, and the most important types associated with 

cervical cancer after HPV 16 and 18. 

A five-and-a-half-year follow-up view of the data using Kaplan-Meier curves shows that even 

during the latter part of the follow-up period, there is continued accrual of cases at a higher 

rate in the placebo arm than in the vaccine arm, especially for HPV 45. Point estimates of 

efficacy remain similar to what they were with shorter-term follow-up, suggesting that, for 

these endpoints, there's no waning of the effect previously reported. These data will be 

supplemented with additional data from the Phase III results. 

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Global ranking of HPV types in terms of their importance in cervical cancer indicates that 

HPV 45 and 31 are responsible for about 10 percent of cancers after HPV 16 and 18. 

Together, these four types are responsible globally for about 80 percent of cancers.

 

Dr. Dubin then discussed GSK’s overall, ongoing clinical development program, focusing on 

immunogenicity studies that allow age bridging using immunological criteria. HPV-009 is a 

collaborative study conducted in Costa Rica with the National Cancer Institute. It has 

enrolled about 7500 women and is in ongoing follow up. The largest single HPV efficacy 

study conducted to date is HPV-008, with over 18,000 subjects enrolled. GSK hopes to 

present those results at the next open meeting. 

HPV-015 is an efficacy study in women over 25 years of age. GSK believes that the vaccine 

is ultimately going to be important in this age category. It is already relatively clear that new 

incident infections can occur in women in the age range of 25 years and up. Even though the 

rates are lower than in younger women, they're still substantial. There are also some data to 

suggest that new infections are more likely to become persistent with increasing age. GSK’s

target is that HPV vaccination be accessible to women who are over the age of 25 years; right 

now, using HPV vaccination in an older age range would be considered off label. 

 

HPV-014 bridges antibody responses in girls 15 to 25 years to antibody responses in women 

over the age of 25 years. It was conducted in Germany and Poland, and enrolled over 600 

subjects. Immunobridging was conducted in an age-stratified manner. The same three-dose 

schedule was used and data are now available through the Month 18 time point, which 

represents the inflection in the kinetic curve of antibody responses where responses begin to 

plateau. GKS believes that what is seen in Month 18 is predictive of what will likely come in 

longer-term follow up. 

Geometric mean antibody titers for HPV 16 and 18 differ in each of the age strata, with a 

tendency to decrease in women in the older age strata. This is expected based on an 

understanding of other vaccines and probably represents, to a limited extent, senescence of the 

immune system over time. Nonetheless, high antibody titers are seen in all age strata 

evaluated for both serotypes. Virtually all vaccinated women were seropositive regardless of 

the age strata for both types in this study. In fact, all women were seropositive after the 

second dose. 

An issue is how to interpret immunogenicity data in the context of this study since there is no 

established correlate of protection. Even though a minimum protective threshold has not yet 

been defined, it seems relevant to look at data generated in the efficacy study just shown 

because there is now evidence that when antibody levels are maintained in this plateau phase, 

a high level of protection is observed. This appears to provide a biologically relevant 

threshold with which to compare antibody responses, and responses that are similar or greater 

to responses seen in the long-term phase of the efficacy study appear likely to predict 

protection. 

 

 Data on antibody levels from the five-and-a-half-year follow-up period of the efficacy study

show the same plateau phase through the latter time points. When the geometric mean 

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78

antibody titers from the immunobridging study are superimposed over those from the followup efficacy study, they appear quite similar, despite small differences in the responses in each 

of the age strata. These titers very likely correlate with protective titers, at least at this time 

point, and because of the kinetics of the response after Month 18, the pattern should be 

predictable for some of the latter time points. Results for HPV 18 look almost identical. 

 Regarding the safety profile in women in this study, there are no significant differences in 

reactogenicity observed in the older age strata compared with the 15-25 year age stratum. In 

fact, for many of the symptoms, there appears to be lower reactogenicity as the age strata 

advances. 

In conclusion, the candidate vaccine appears to be generally well tolerated in all age ranges 

evaluated. There is evidence of a high level of efficacy against HPV-16 and -18 endpoints 

with complete protection against CIN lesions over the five-and-a-half year period, which uses 

all of the data generated to date in this study. When comparing the efficacy levels in the latter 

part of the follow-up period with the earlier part of the follow-up period, there is no evidence 

of waning protection. This study provides preliminary evidence that the vaccine is able to 

protect against incident infection with the most relevant non-vaccine types, and the hope is 

that these data can be extended in the Phase III studies. Finally, the immunobridging 

objectives for the 014 study were met, and antibody titers in women over the age of 25 

appeared to be in the same range as titers that correlate with protection in the efficacy study. 

 Dr. Dubin briefly described the large, pivotal Phase III efficacy study mentioned at the 

beginning of the session. This is a large, double-blind, randomized trial. The subjects were 

randomized to receive the GSK vaccine or hepatitis A vaccine, which is used as a control. 

The same zero-, one-, and six-month schedule is used, and subjects are followed virologically 

and for histopathologic endpoints. Over 18,000 women between the ages of 15 and 25 were 

enrolled between May 2004 and June 2005. Fourteen countries participated in four regions of 

the world, and there was an event-triggered interim analysis, which will evaluate efficacy 

against CIN 2-plus endpoints associated with vaccine types. The required number of events 

was accrued toward the end of last year. The analysis is near completion, and GSK hopes to 

present data in the near future. 

 Before closing, Dr. Dubin mentioned that regulatory files have been submitted for this 

vaccine in a number of countries, including the E.U. GSK plans to submit a U.S. BLA by 

April of this year. It has already initiated a fairly large Phase IIIb program. Some of the most 

important studies include the efficacy study conducted in women over the age of 25 years, 

some studies evaluating co-administration with commonly used vaccines in this age range, the 

safety and immunogenicity trial in HIV-positive women, which will begin later this year, and 

other trials being conducted in countries for registration purposes. GSK plans to do a Phase 

IV study in Finland, which will actually involve long-term follow up of a large cohort of 

women enrolled in the Phase III program. It has a community randomized trial, which is well 

advanced in the planning stages, to evaluate induction of herd immunity and population 

impact of HPV vaccination, and other Phase IV studies are under development. 

 

Discussion

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Dr. Baker asked whether there were plans for pregnancy follow up. Dr. Dubin replied that 

there is active surveillance for pregnancy outcomes in a number of the planned Phase IV 

studies. GSK will also be doing passive surveillance in the U.S., using a pregnancy registry. 

 

Dr. Kathy Neuzil noted that the cross-protection data will be important from a populationimpact standpoint and asked how related these viruses might be and if GSK was proposing an 

antigenic-relatedness hypothesis. Dr. Dubin responded that HPV 45 is one of the closestrelated viruses to HPV 18, and HPV 31 is closely related to HPV 16. So if one were to 

analyze the L-1 protein sequences and try to predict, based on understanding of neutralizing 

epitopes, which types might actually be expected to be protected against because they're 

phylogenetically related, these two types would probably be near the top of the list. However, 

the mechanism of cross-protection is not known, whether it is mediated by neutralizing 

antibody responses that have the ability to cross-neutralize related types or whether it is 

related to T-cell responses. Studies are under way to try to better understand the mechanism. 

Dr. Eliav Barr from Merck added that an amino acid sequence is just the linear sequence of 

the amino acids of the protein, and the antibodies generated by vaccines really relate to 

quaternary structures or the way they're folded up. Although the amino acid sequence is a 

convenient way to look at how things relate, one cannot say which type is closest on an 

epitope basis or on the face of the VLP or the face of the virion. The way to evaluate this is 

efficacy-based because the immunology of HPV is not very well understood. 

 

Dr. Winston Price, National Medical Association, asked how many older women were going 

to be involved in the immunobridging study. He also expressed concern about the lack of 

long-term studies being carried out on the continent of Africa or in the Caribbean. It's very 

critical in the U.S. to understand the importance of the vaccine in minority populations. Dr. 

Dubin responded that the Phase III studies have been conducted in a very broad range of 

countries. For example, in the largest efficacy study, HPV-008, about a third of the enrolled 

subjects were in Asia. Some of the other Phase III studies enrolled large numbers in Central 

America and South America. GSK is planning to initiate a relatively large immunobridging 

study in at least two and possibly three countries in Africa, if the logistics can be set up. 

Having broad geographic representation is important because countries that have a large 

burden of cervical cancer disease must have rapid access to the vaccine and it is important to 

understand whether or not the vaccine will behave similarly in these populations. Regarding 

the proportion of women over the age of 25 in GSK’s development program, the 

immunobridging study described is relatively small with about 600 subjects enrolled. The 

efficacy program has focused on 15- to 25-year-old women. The strategy has been to first 

generate immunobridging data in younger and older women. However, there is an ongoing 

efficacy study that includes women over the age of 25, and that study has enrolled over 5700 

women. Based on some of that data, the picture is becoming clearer about whether the 

vaccine is likely to provide protection to women in this age range. 

Quadrivalent HPV Vaccine Update

Dr. Lauri Markowitz gave an overview of various aspects of HPV vaccine, including 

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recommendations, the Vaccines for Children (VFC) program, vaccine distribution, postlicensure safety data, plans for monitoring vaccine impact, and school mandates. The ACIP 

voted in June 2006to recommend the HPV vaccine, and provisional recommendations were 

posted on the Web in July of that year. The ACIP statement will be published in April 2007, 

and it will be available online probably in mid-March. 

The VFC resolution was adopted at the June 2006 ACIP meeting. A federal contract was 

established for the vaccine in October 2006. An excise tax was added after the vaccine was 

included in the National Vaccine Injury Compensation program, and the current contract price 

for the vaccine is $96.76 a dose. Quadrivalent HPV vaccine doses distributed in the U.S. were 

estimated at about 2.1 million doses through the end of December 2006, and about 40 percent 

of these doses were purchased with public-sector funds. 

With regard to post-licensure safety, the first data are from the Vaccine Adverse Events 

Reporting System, or VAERS. These data were provided by the Immunization Safety Office 

at CDC, and they are through the end of January 2007. VAERS is one of the cornerstones of 

post-licensure surveillance activity. This is a national, spontaneous reporting system operated 

jointly by CDC and FDA, and although VAERS has well-described limitations, including 

underreporting and inability to determine a causal relationship, it does allow hypothesis 

generation. 

Through the end of January 2007, 542 events for HPV vaccine were reported to VAERS. The 

overall reporting rate was about 25 per 100,000 doses, which is slightly higher than the 

overall average for most vaccines, but it's not unexpected for a new vaccine that providers are 

not familiar with. As expected, 99 percent of the reports were in females, and 47 percent 

were in individuals 13 to 18 years of age. About 5 percent of all the reports were designated 

as serious, and no deaths were reported. The most common symptoms reported to VAERS 

after quadrivalent HPV vaccine were injection-site pain, dizziness, syncope, fever, and 

nausea. Among the cases of syncope, there were three nose fractures, and one girl, who had a 

history of a seizure disorder, fainted, hit her head, and had a seizure. 

There are many previous published reports of syncope after vaccination of adolescents, and 

the ACIP general recommendations statement does say that syncope can occur after 

vaccination, most commonly in adolescents and young adults. A precaution about this has 

been included in the ACIP HPV-vaccine statement, as well as a recommendation that 

providers should consider observing patients for 15 minutes after vaccination. 

There were three cases of Guillain Barré Syndrome reported and three cases of facial palsy. 

For the Guillain Barré cases, one case occurred after administration of HPV vaccine alone, 

and the onset date postvaccination was not reported. Two cases occurred after HPV vaccine 

and MCV4 administration. Because of the small number of cases, a formal observed versus 

expected calculation has not been done, and the Immunization Safety Office will continue to 

monitor this on an ongoing basis. The three cases of facial palsy all occurred within one day 

of vaccination and after different vaccine administrations. Only one occurred after HPV

vaccination alone. The background incidence of facial palsy is about 30 per 100,000 people 

per year, much higher than GBS, so the observed is much less than expected. This will also be 

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monitored with both active and passive systems. 

Data from the Vaccine in Pregnancy registry, managed by Merck, shows 44 exposures to 

vaccine reported through January 10th, 2007, and 38 were enrolled in the registry. Two

women had elective abortions and two had spontaneous abortions. CDC also plans to monitor 

HPV vaccine during pregnancy in the Vaccine Safety Datalink, and those data will be 

presented at future meetings. 

Systems are in place or being developed at CDC to monitor a variety of outcomes, including 

cervical cancer and other HPV-related cancers, HPV prevalence, and cervical cancer 

precursor lesions, such as cervical intraepithelial neoplasia and genital warts. Other 

monitoring systems are also being discussed. The U.S. has an excellent system of cancer 

registries that would be able to track trends in cervical cancer and other cancers related to 

HPV. SEER, the Surveillance Epidemiology and End Results study has been in place since 

1973, and the National Program of Cancer Registries has been in place since 1995. Together 

they cover about 96 percent of the U.S. population. 

Monitoring the impact of HPV vaccine will include a variety of outcomes. In addition to or in 

conjunction with cervical cancer registries, HPV typing will be initiated at several sites in the 

U.S. to allow determination of specific HPV types related to cervical cancers. It will take 

several decades to see any impact of HPV vaccine on cervical vaccine, so some of the more 

proximal outcomes are going to be monitored. Type-specific HPV prevalence is currently 

being monitored in the National Health and Nutrition Examination Survey, or NHANES. 

Self-collected vaginal swabs were added to the survey in 2002, which has allowed 

determination of a population-based prevalence of HPV types. 

Plans are currently in progress to monitor CIN 2/3 through supplemental data collection in 

VSD. CDC also plans to monitor CIN 2/3 through administrative databases, such as MedStat, 

and through new sentinel projects to be initiated to collect population-based data on overall 

and type-specific CIN 2/3. Genital warts will be monitored through a network of STD clinics, 

administrative databases and other sources being developed. 

The issue of school immunization mandates has been well covered in the news media. 

Currently, over 18 states have introduced some type of legislation for school-entry 

requirements for HPV vaccine. Additional states have introduced other types of legislation 

related to education or insurance coverage. No state legislature has passed a bill for school 

immunization mandates at the present time. In Texas, there was an executive order for a 

middle school HPV-vaccination requirement. 

A variety of positions regarding school mandates have been adopted by different professional 

organizations. The Association of Immunization Managers (AIM), whose members include 

representatives from all 64 state, territorial, and local and national immunization program 

grantees, posted the following statement on their Web site in June 2006. "School and 

childcare immunization requirements must be used sparingly, approached cautiously, and 

considered only after an appropriate vaccine implementation period. This vaccine 

implementation period is critical to ensure that the necessary elements are in place to support 

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a school childcare requirement, including: 

• Coverage for the vaccine in private health insurance plans 

• Sufficient funding to purchase the vaccine 

• Physician/provider support for the vaccine 

• Public acceptance of the vaccine 

• Stable and adequate vaccine supply 

• Addition of vaccine to immunization information systems (registries)

• Adequate data to assure vaccine safety 

• Significant uptake in the recommended population to reduce the compliance burden 

on the school/child care system.” 

The work group will continue to review data on both vaccines and HPV epidemiology that 

will be necessary to formulate new recommendations and cost effectiveness, and then 

develop recommendations for options and to revise the ACIP statement as needed. 

Discussion

 

Dr. Abramson asked whether there would be enough money in the system to cover the cohort 

of girls and women who will get the vaccine, about half of whom are covered by VFC, and 

whether AIM’s problems in prioritizing different groups would be avoided. Dr. Schuchat 

addressed the VFC part of the question. There is a contract and financing in place for the 

VFC population. The money is provided per request based on estimates of the population that 

needs it, so financing should not be an issue for the 9- to 18-year-old girls who are VFC 

eligible (approximately 45% of each birth cohort). VFC covers uninsured children, people 

who are Medicaid eligible, native Americans, Alaska natives, and underinsured persons 

seeking care at a federally qualified health center or rural health center, but a large population 

is not VFC eligible. Dr. Markowitz added that AIM repeated the survey presented at the 

October meeting, so there may be some additional changes in those findings. Ms. Hannan 

added that out of 53 survey responses, only four have not implemented VFC in 9- to 18-yearolds. But this is not all public financing, and there are still the under-insured to consider. 

 

Dr. Schuchat commented that the VFC program has been a tremendous resource for children, 

also helping states and providers provide appropriate care. A challenge has been the focus on 

young children and strengthening provider-program relationships. However, VFC funding 

has recently been obtained for states to hire adolescent coordinators to help enroll providers 

who care for adolescents. This will help with quality control, enrollment, and management 

and storage of vaccines and administration of vaccines in this new provider group. 

 

Dr. Susan Lett noted that because of the lack of adequate reimbursement in the private sector, 

some doctors are not able to offer the vaccine to under-insured patients. Many are referred to 

clinics and public health centers, but not all those children are VFC eligible, which puts stress 

on the public health system. However, states have been able to increase their allocation of 

doses to VFC-eligible girls. Dr. Baker requested clarification about the difference between 

VFC-eligible and VFC-enrolled. Dr. Schuchat responded that when the VFC program was 

established, the provider was supposed to determine who was eligible. However, many 

children who were eligible for Medicaid were not enrolled. VFC makes it very simple for the 

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provider to not miss an opportunity to vaccinate. 

 

Dr. Treanor wondered if there were other vaccines for diseases that would not specifically be 

transmitted within the classroom and for which there are school mandates, such as hepatitis B. 

In other words, is using a mandate to increase vaccination rates rather than prevent 

transmission of diseases within the classroom a new concept? Dr. Schuchat replied that 

hepatitis B vaccine has had many school mandates, and that both mandates aim to reduce 

transmission within the classroom and assure herd protection with high coverage rates. Dr. 

Treanor felt this philosophy seemed to extend to boundaries of the original intent of mandates. 

 

Dr. Rick Haupt from Merck expressed his pleasure with ACIP and others’ support and the 

remarkable uptake of Gardasil. Merck’s goal has been to have the broadest potential impact 

and use of this vaccine in the appropriate populations, especially underserved and poor 

populations, those missed in screening. As such, Merck supported school requirements 

initially at the state level, which increased funding and access to the vaccine. However, based 

on ongoing discussions with many different stakeholders and the perception this may be a 

distraction from getting women vaccinated, Merck is suspending its lobbying efforts for 

school requirements at this time. It will continue to provide information about HPV and the 

vaccines and advocate for public health programs that provide education about cervical cancer 

as well as screening and funding for vaccines at the state level. Lastly, Merck would oppose 

any legislation that would restrict access to Gardasil. 

Dr. Morita added that the original intent of school-entry laws was to decrease transmission in 

the school setting, but in places with disparities issues, they also serve as a safety net, catching 

children who might slip through the cracks and not get their immunizations. Evidence from a 

small study suggested that by the time of school entry, African-American and Hispanic kids 

do catch up, possibly because of the school mandates. So there is a role for HPV mandates, 

but not necessarily right now. 

 

Dr. Susan Lett agreed that states need to go through their normal processes. The AIM position 

statement talks about how do a school mandate carefully and correctly, making sure there's an 

adequate supply; a good post-licensure safety track record; working with insurers on 

reimbursement; and convening public hearings with stakeholders to assure buy-in. 

 

Ms. Stinchfield said that the issues around mandates were confusing and inconsistent. The 

traditional reason was reducing the infections that are spread in the classroom, but now people 

are talking about equity. Why is there no mandate for TDaP when there is pertussis all over 

the country? Why is there no influenza mandate? Another issue is that these are unfunded 

mandates. If they are so important, the resources need to be there. Dr. Amy Middleman, 

Society for Adolescent Medicine, added that school mandates are important currently in the 

absence of strong immunization platforms. Evidence from the March study indicates that in 

states that had school mandates for hepatitis B, adolescent completion rates are approximately 

75 percent versus 39 percent in states without mandates. 

 

Dr. Rick Zimmerman stated that he supports mandates for measles and pertussis vaccines 

because of the risk that one child could expose another who either didn't respond to vaccine or 

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had a legitimate contraindication. Smallpox and measles were examples where that was a real 

risk. There has been transmission of hepatitis B among wrestlers, through dialysis, and 

among preschoolers. However using the argument that the end justifies the means is 

undesirable, given the history of issues related to government rules and eugenics in this 

country and others. 

 

Dr. Sam Katz suggested looking at the state of Washington’s program, which has an 

immunization action committee. They consider every new vaccine individually, and have 

nine points under which they consider whether there should be a mandate. Dr. Georges Peter, 

from Brown Medical School, added that the National Vaccine Advisory Committee had 

developed a paper entitled, "Public Health Options for Implementing Vaccine 

Recommendations." He felt it would be helpful in terms of providing a national framework. 

In addition, Dr. Peter expressed concerns about global use of this vaccine. This country is 

committed to a three-dose schedule, but the vaccine is expensive and also highly 

immunogenic. He asked if there had been consideration of alternative schedules, such as twodose schedules, which would obviously greatly reduce the cost globally, and expressed his 

hope that companies would be open to that option. Dr. Abramson said he thought the twodose schedule had already been considered by the committee. Dr. Markowitz responded that 

the two-dose recommendation had not been seriously considered for the U.S., but that there 

had been considerable interest globally, including the World Health Organization. 

Dr. Schuchat commented that one of the many things that can be looked at post licensure in 

the surveillance and effectiveness activities is partial schedules. The pneumococcal conjugate 

vaccine effectiveness paper recently reported high efficacy of partial schedules, given that 

there was a shortage and a lot of people didn't get the full schedule. 

Ms. Claire Hannan expressed her hope that the committee would further the discussion and 

bring groups together to talk about how school mandates can be used in the best way. She 

also mentioned the philosophical exemption, which many school laws are allowing. When 

considering how to mandate new vaccines, allowing an exemption where one doesn't exist 

could compromise the existing mandate. 

 

Dr. Mark Feinberg, Merck Vaccine Division, was concerned that access and equity issues 

were getting lost in the discussion about school requirements. The ACIP issued its unanimous 

universal recommendation last June, which basically set the parameters of the public health 

goal. Presumably, the best public health achievement would be having those recommended to 

receive this vaccine get it as soon as possible to have the maximum public-health benefit, 

because there are millions of cases of HPV infection each year and 10,000 cases of cervical 

cancer. But it is more likely that certain segments of the population will get access to the 

vaccine and others will lag far behind. Unfortunately, the ones most likely to lag behind are 

those in racial and ethnic minority groups and economically disadvantaged individuals. 

Dr. Feinberg said Merck has actively advocated at the state level for increases in state general 

funds and for Medicaid coverage of this vaccine for eligible populations. It has been an active 

member of the 317 coalition, which has lobbied at the state level to fight against the $100 

million cut in the 317 project that was proposed by the President's budget last year and has 

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85

been increased, fortunately, by $32 million this year. Merck has also instituted a patientassistance program, providing the vaccine free of charge to all low-income individuals less 

than 200 percent of the federal poverty limit, who cannot afford this vaccine and don't have 

insurance. 

With respect to access on the global scale, Merck is committed to providing its vaccine in an 

affordable and sustainable manner, working with partners such as PATH to look at alternative 

immunization approaches in developing countries. It has committed over $15 million worth of 

Gardasil specifically for projects in collaboration with PATH. Merck is very interested in 

working with ACIP to address access and equity issues. Dr. Duchin pointed out that the 

Merck program to provide vaccine to the people below 200 percent of the poverty level is not 

available to local or state health departments where many of these women seek care. 

AGENCY UPDATES

CDC/CCID/NCIRD

Dr. Schuchat informed the group that in January this agency announced, in conjunction with 

the WHO, U.N. Foundation, UNICEF, and the American Red Cross, the global goal to reduce 

worldwide measles deaths by 50 percent by 2005 was not only achieved, it was exceeded, and 

deaths were reduced by 60 percent. In Africa, 217 million children in 41 priority countries 

were vaccinated against measles. A new goal, 90 percent worldwide reduction of measles 

deaths by 2010, has been established. 

 

CMS 

Ms. Linda Murphy reported that CMS continues to work with CDC and other agencies on 

pandemic influenza, with a particular emphasis on work between Medicare and Medicaid. 

FDA

Dr. Norm Baylor stated that FDA would convene a meeting of the Vaccines and Related 

Biological Projects (VRBPAC) coming up February 27th and 28th, in Gaithersburg, Maryland. 

Evaluation of a new vaccine against H5N1, a potential pandemic influenza strain, will be 

presented. A discussion on the clinical development of influenza vaccines for pre-pandemic 

use will be held to decide on a strain selection for the 2007-2008 influenza season, including 

whether to include a second B strain in the vaccine. 

At the January 25 meeting of VRBPAC, licensure of Pentacel was discussed. Results for a 

Hib component were inconsistent. In one trial, a reduction of Hib in the group that received 

Pentacel was seen. In the second study, similar responses to the Hib component in Hib versus 

the Pentacel were seen, but there was a rarer response than seen in the first study, so there are 

some concerns about the response to Hib with the vaccine. The statistical criteria for the 

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86

response to the protective antigen in the pertussis component seemed shallow. 

HRSA

 

Dr. Indira Jevaji presented an update on thimerosal and autism and another update on 

congressional activity. As of January 3, 2007, there were 5100 thimerosal-autism claims filed 

with the National Vaccine Injury Compensation Program. In 2001 or 2002, the Chief Special 

Master of the U.S. Court of Federal Claims ordered the process for adjudicating these claims, 

called the Omnibus Autism Proceedings. This process involves adjudicating petitions filed by 

the ACIP, the VICP and others from either MMR vaccine or thimerosal-containing vaccines. 

Phase I of the Omnibus Proceedings is coming to an end. It involves an extensive discovery 

process, however, petitioners have recently submitted a motion for additional discovery, 

which has been approved by the courts. The deadline for submission of the petitioners’ 

experts was February 16, 2007. The next step is a hearing on entitlement to compensation, 

which is scheduled for June 2007. 

Recently, the petitioners declared a desire to modify the hearing on entitlement and schedule 

of rates. First, instead of conducting a hearing in an omnibus fashion, the petitioners 

indicated their intent to establish causation in test cases. Rather than bringing evidence on all 

theories in June 2007, the petitioners now want to limit the first hearing to the sole issue of 

MMR/thimerosal as the cause of autism. Finally, the Chief Special Master issued a notice on 

January 11, 2007, indicating that two additional Special Masters will be assigned to hear and 

decide the issues presented in the test cases. 

Regarding congressional activity, on December 20, 2006, the President signed the Tax Relief 

and Healthcare Act of 2006, which added meningococcal vaccines -- both conjugate and 

polysaccharide -- and the HPV vaccines to the list of taxable vaccines. There are two 

prerequisites for vaccine coverage by the VICP: the imposition of the excise tax and MMWR

publication of a CDC recommendation for routine use in children. Both requirements have 

been satisfied for the meningococcal vaccines. However, the HPV vaccine will be covered 

once the CDC publishes the ACIP statement in the MMWR publication. Finally, some 

meningococcal vaccines will be added to the vaccine injury table under the general category. 

NIH 

Dr. Curlin apologized for not having the Jordan Report, as expected, but promised to see that 

all liaison members and members of the ACIP receive a copy. Anyone else can request a 

copy by email. The Jordan Report is an occasional document from NIH about vaccine 

research and development activities, largely funded by NIH. There's a considerable amount of 

good vaccine research and development in the pipeline and NIH’s perspective is just a small 

pass at the total picture. The Report will probably be reformatted in the future. 

 

NVPO and NVAC

 

Dr. Bruce Gellin reported that at NVAC, there's discussion of HPV vaccine and highlights of 

the work of the Adolescent Working Group, which has been asked by the Assistant Secretary 

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87

of Health to define the problem statement. A paper is working its way through before 

solutions are sought. There's also an active Vaccine Financing workgroup, which will feed 

into a discussion in Chicago. Results of that meeting will be presented because financing is 

relevant and comes up frequently. 

At NVAC, the recommendation on registries has been approved and publication is 

forthcoming. Work on pandemic vaccine prioritization has already been reported. When the 

draft guidance is available, it is hoped that this committee in its full capacity, as well as 

individuals and the organizations they represent, will provide feedback. There will also be a 

public-comment period. Finally, a long-overdue effort is to update the 1994 national vaccine 

plan. 

Closing Session 

Dr. Abramson thanked the participants for attending the meeting. With no further discussion 

or business brought before ACIP, Dr. Abramson adjourned the meeting at 12:03 p.m. on 

February 22, 2007. 

I hereby certify that to the best of my 

knowledge, the foregoing Minutes of the 

February 21-22, 2007 ACIP Meeting are 

accurate and complete.

_______________________ _________________________________ 

Date Jon S. Abramson, M.D., Chair, 

Advisory Committee on Immunization 

Practices

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88

P A R T I C I P A N T S

CHAIR

JON S. ABRAMSON, M.D.

Weston M. Kelsey Professor and Chair, 

Department of Pediatrics

Wake Forest University School of Medicine, 

Winston-Salem, North Carolina

EXECUTIVE SECRETARY

LARRY K. PICKERING, M.D.

Senior Advisor to the Director, National 

Immunization Program 

Centers for Disease Control and Prevention, 

Atlanta, Georgia

 

ACIP MEMBERS

BAN MISHU ALLOS, M.D.

Assistant Professor, Division of Infectious Diseases

Vanderbilt University School of Medicine, 

Nashville, Tennessee

CAROL BAKER, M.D.

Professor of Pediatrics, Molecular Virology and 

Microbiology

Baylor College of Medicine, Houston, Texas

MR. ROB BECK

Palmyra, Virginia

JANET R. GILSDORF, M.D.

Director, Pediatric Infectious Diseases, Department 

of Pediatrics and Communicable Diseases

University of Michigan, Ann Arbor, Michigan

HARRY HULL, M.D.

State Epidemiologist and Director

Minnesota Department of Health, Minneapolis, 

Minnesota

SUSAN LETT, M.D., M.P.H.

Medical Director, Massachusetts Department of 

Public Health

Jamaica Plain, Massachusetts

TRACY LIEU, M.D.

Associate Professor of Ambulatory Care and 

Prevention

Harvard Pilgrim Healthcare and Harvard Medical 

School, Boston, Massachusetts

JULIE MORITA, M.D.

Medical Director, Immunization Program

Chicago Department of Health, Chicago, Illinois

DALE L. MORSE, M.D.

Director, Office of Science and Public Health

New York State Department of Health, Albany, 

New York

KATHLEEN NEUZIL, M.D., M.P.H.

Clinical Associate Professor of Medicine

University of Washington, Seattle, Washington 

PATRICIA STINCHFIELD, NP

Director, Pediatric Infectious Disease and 

Immunology

Children's Hospitals and Clinics of Minnesota, St. 

Paul, Minnesota 

CIRO VINCENT SUMAYA, M.D., M.P.H.

School of Rural Public Health

Texas A&M University System Health Science 

Center, College Station, Texas

JOHN J. TREANOR, M.D.

Associate Professor of Medicine

University of Rochester, Rochester, New York

EX OFFICIO MEMBERS

NORMAN BAYLOR, Ph.D.

Food and Drug Administration, Rockville, 

Maryland

JAMES E. CHEEK, M.D.

National Epidemiology Program, Indian Health 

Program, Albuquerque, New Mexico

GEORGE CURLIN

Medical Director, National Institutes of Health, 

Bethesda, Maryland

BRUCE GELLIN, M.D.

Director, National Vaccine Program Office, 

Washington, D.C.

WAYNE HACHEY, DO, M.P.H.

Department of Defense, Falls Church, Virginia

INDIRA JEVAJI, M.D.

Medical Officer, Division of Vaccine Injury 

Compensation

HRSA, Bureau of Health Professions, Rockville, 

Maryland

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89

LINDA MURPHY

Centers for Medicare and Medicaid Services, 

Baltimore, Maryland

KRISTIN NICHOL, M.D. 

Chief of Medicine, VA Medical Center, 

Minneapolis, Minnesota

LIAISON REPRESENTATIVES

American Academy of Family Physicians

DOUG CAMPOS-OUTCALT, M.D.

University of Arizona, College of Medicine, 

Phoenix, Arizona

JONATHAN TEMTE, M.D.

Family Practice Residency Program, Madison, 

Wisconsin

American Academy of Pediatrics

JOSPEH A. BOCCHINI, JR., M.D.

Children's Hospital of LSU, Shreveport, Louisiana

America's Health Insurance Plans

TAMARA LEWIS, M.D., M.P.H.

Medical Director, Intermountain Healthcare, Salt 

Lake City, Utah

American College Health Association

JAMES C. TURNER, M.D.

Director, Elson Student Health Center

University of Virginia, Charlottesville, Virginia

American College of Physicians

SANDY FRYHOFER

American Medical Association

LITJEN TAN, Ph.D.

Director, Infectious Diseases, Immunology, & 

Molecular Medicine

Chicago, Illinois

American Osteopathic Association

STANLEY E. GROGG, D.O.

Oklahoma State University. Tulsa, Oklahoma

American Pharmacists Association

STEPHAN L. FOSTER, Pharm.D.

University of Tennessee, Memphis, Tennessee

Association of Teachers of Preventive Medicine

W. PAUL MCKINNEY, M.D.

Professor and Chief, Division of Internal Medicine

University of Louisville, Louisville, Kentucky

Biotechnology Industry Organization

CLEMENT LEWIN, Ph.D., MBA

Executive Director for Strategic Planning & 

Intelligence

Chiron Vaccines, Orange, Connecticut

Canadian National Advisory Committee on 

Immunization

MONIKA NAUS, M.D.

Associate Director, Epidemiology Services, 

Vancouver, BC, Canada

Healthcare Infection Control Practices Advisory 

Committee

STEVE GORDON, M.D.

Cleveland Clinic, Cleveland, Ohio

Infectious Diseases Society of America

SAM KATZ, M.D. 

Wilbert C. Davison Professor 

Duke University Medical Center, Durham, North 

Carolina

London Department of Health

DAVID M. SALISBURY, M.D.

Director of Immunization, Department of Health. 

London, UK

National Association of County and City Health 

Officials 

NANCY BENNETT, M.D. 

Director, Center for Community Health

University of Rochester School of Medicine and 

Dentistry, Rochester, New York

JEFFREY DUCHIN, M.D.

Chief, Communicable Disease Control, Seattle, 

Washington

National Foundation for Infectious Diseases

WILLIAM SCHAFFNER, M.D.

Professor and Chairman, Vanderbilt University 

School of Medicine

Nashville, Tennessee

National Immunization Council and Child Health 

Program, Mexico

VESTA RICHARDSON, M.D.

General Director, National Center for Health and 

Infancy and Adolescence

Colonia Merced Gomez, Mexico

National Medical Association

WINSTON PRICE, M.D.

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National Vaccine Advisory Committee

GARY FREED, N.D., M.P.H.

Division of General Pediatrics, University of 

Michigan, Ann Arbor, Michigan

Pharmaceutical Research and Manufacturers of 

America

DAMIAN A. BRAGA

President, sanofi pasteur - U.S., Swiftwater, 

Pennsylvania

PETER PARADISO, M.D.

Vice President, Wyeth Vaccines, Collegeville, 

Pennsylvania

Society for Adolescent Medicine

AMY B. MIDDLEMAN, M.D., M.P.H. 

Baylor College of Medicine, Texas Children's 

Hospital, Houston, Texas

Society for Healthcare Epidemiology of America

HARRY L. KEYSERLING, M.D.

Professor of Pediatrics, Emory University, Atlanta, 

Georgia

Other Registered Attendees

Brian Abraham, Wyeth, Collegeville, PA

Vincent Ahonkhai, GlaxoSmithKline 

Pharmaceuticals, Prussia, PA

Maria Allende, MedImmune, Gaithersburg, MD

Stephen Allred, Get A Flu Shot.com. Portland, OR

Jennifer Armstrong, GlaxoSmithKline, 

Philadelphia, PA

Phyllis Arthur, Merck & Co. Inc., Lansdale, PA

Yaela Baine, GSK Biologicals, Prussia, PA

Allyn Bandell, MedImmune, Denver, CO

Eliav Barr, Merck Research Laboratories, Merck & 

Co., North Wales, PA

Karen Beauvais, Generation Rescue, Atlanta, GA

Shayne Bevilacqua, GSK Biologicals, Philadelphia, 

PA

Joan Benson, Merck & Co. Inc., PA

Karyn Berry, District of Columbia Depattment of 

Health

Donna Boyce, GlaxoSmithKline Pharmaceuticals, 

Prussia, PA

Lena Bretous, SC Department of Health and

Environmental Control, Columbia, SC

Dennis Brooks, Merck & Co., Inc. West Point, PA

Prakash Buyan, Merck & Co., Inc., North Wales, 

PA

Delvin Carmel, Wyeth, Pearl River, New York

Donna Cary, sanofi pasteur, Swiftwater, PA

Michael Channey, GA Chapter, American 

Academy of Pediatrics

Jody Clark, Wyeth Pharmaceuticals, Prussia, PA

Liana Clark. Merck & Co. Inc., West Point, PA

Richard Clover, University of Louisville, 

Louisville, KY

Kathleen Coelingh, MedImmune Vaccines, Helena, 

CA

Edward Connor, MedImmune, Gaithersburg, MD

Lenore Cooney, Cooney/Waters Group, New York, 

NY

Gerard Cunningham, Merck & Co. Inc., West 

Point, PA

Donald Dalrymple, Dalrymple & Associates, 

Washington, DC

Adrian Dana, Merck & Co., Inc., North Wales, PA

Ana Dayton, Constella Group, Rockville, MD

Carolyn Deal, National Institute of Allergy and 

Infectious Diseases, Bethesda, MD

Anna DeBlois, Association of State and Territorial 

Health Officials, Washington, DC

Machael Decker, sanofi pasteur, Swiftwater, PA

Shelly Deeks, Public Health Agency/Immunization 

and Respiratory Infections Division, Toronto, 

Ontario, Canada

Penelope Dennehy, Rhode Island Hospital, 

Providence, RI

Christine Dingivan, MedImmune, Inc., 

Gaithersburg, MD

Richard Dinovitz, Wyeth Pharmaceuticals, 

Collegeville, PA

Gary Dubin, GlaxoSmithKline, West Chester, PA

Colleen Duffy, Merck Vaccine Division, West 

Point, PA

Eric Easom, MedImmune, Gaithersburg, MD

Laurel Edelman, Surveillance Data Inc., Plymouth 

Meeting, PA

Elamin Elbasha, Merck & Co., Inc., North Wales, 

PA

Geoffrey Evans, Division of Vaccine Injury 

Compensation, HRSA, Rockville, MD

Christine Fanelle, Merck & Co., Inc., West Point, 

PA

Mark Feinberg, Merck & Co., Inc., West Point, PA

Erica Flagg, GSK Biologicals, Philadelphia, PA

Stephen Ford, Military Vaccine Agency, Falls 

Church, VA.

John Frazzette, Merck & Co., Inc., West Point, PA

Leonard Friedland, GSK Biologicals, Prussia, PA

Gerald Gabor, Wisconsin Immunization Program, 

Madison, WI

Mary Gadek, Novartis, Philadelphia, PA

Lara Gain, sanofi pasteur, Orange Park, FL

Stanley A. Gall, American College of Obstetricians 

& Gynecologists, Glenview, KY

Patrick Garmon, Department of Defense, Fort 

White, FL

Matthew Garrett, Wyeth Vaccines, Collegeville, 

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PA

Diana Gaskins, Division of Public Health, Georgia 

Immunization Program, Atlanta, GA

Bruce Gellin, DHHS, National Vaccine Program 

Office, Washington, DC

Gregory Gilmet, sanofi pasteur, Swiftwater, PA

Ruth Gilmore, Georgia Immunization Program, 

Atlanta, GA

Steven Goldberg, Constella Group, Rockville, MD

Karen Goldenthal, Pharmanet Consulting, 

Bethesda, MD

Jesse Greene, SC Department of Health and 

Environmental Control, Columbia, SC

David Greenberg, sanofi pasteur, Swiftwater, PA

Amy Groom, Indian Health Service, Albuquerque, 

NM

Jessie Groothuis, MedImmune, Gaithersburg, MD

Dalya Guris, Merck & Co., Inc., North Wales, PA

Jeff Hackman, Emergent BioSolutions, 

Gaithersburg, MD

Neal Halsey, Johns Hopkins, Baltimore, MD

Sandra Hammer, California Department of Health 

Services, Immunization Branch, Richmond, CA

Claire Hannan, Association of Immunization 

Managers, Rockville, MD

Janice Hashimoto, Novartis, Emeryville, CA

Winnie Hatten, Merck Vaccine Division, 

Schaumberg, IL

Richard Hauber, Bear Stearns, London, UK

Richard Haupt, Merck & Co., Inc., West Point, PA

Philip Hosbach, sanofi pasteur, Swiftwater, PA

Florence Joun, FDA, Rockville, MD

Barbara Howe, GlaxoSmithKline, Prussia, PA

Micki Hultquist, MedImmune, Gaithersburg, MD

Melonie Jackson, Merck, Villa Rica, GA

David Johnson, sanofi pasteur, Swiftwater, PA

Stephen Kay, Generation Rescue, Powder Springs, 

GA

Linda Kelly, SC Dept of Health and Environmental 

Control, Columbia, SC

Peter Khoury, Baxter Healthcare Corporation, 

Beltsville, MD

David Kimberlin, AAP Committee on Infectious 

Diseases, Birmingham, AL

Chester Kitchen, Merck & Co., West Point, PA

Ariyapadi Krishnaraj, Novartis, Philadelphia, PA

Denise Kruzikas, GlaxoSmithKline, Philadelphia, 

PA

David Kuczenski, Lifescience Dynamics, New 

York, NY

Barbara Kuter, Merck & Co., Inc., West Point, PA

Karen Lancaster, MedImmune, Gaitherburg, MD

Sarah Landry, GlaxoSmithKline, Washington, DC

Philip LaRussa, Columbia, University, Division of 

Pediatric Infectious Diseases, New York, NY

Scott Laster, Autism Parent, Alpharetta, GA

Jennifer Lastinger, Families Fighting Flu, 

Grapevine, TX

William La Via, MedImmune, Pacific Palisades, 

CA

Maria-Michele Leger, American Academy of 

Physician Assistants, Alexandria, VA

Edward Lewin, MedImmune, Inc., Gaithersburg, 

MD

Liad Diamond, GSK Biologicals, Philadelphia, PA

Jennifer Lichtner, Wyeth, Collegeville, PA

Parthiv Mahadevia, MedImmune, Gaithersburg, 

MD

Frank Malinoski, MedImmune, Gaithersburg, MD

Laura Martinez, sanofi pasteur, Fort Worth, TX

Dean Mason, Wyeth, Collegeville, PA

Marie Mazur, CSL Biotherapies, Prussia, PA

Diana McGowan, Families Fighting Flu, Nazareth, 

PA

Cody Meissner, Tufts-New England Medical 

Center, Boston, MA

Lynne Mercedes, Georgia Division of Public 

Health, Atlanta, GA

Jacqueline Miller, GlaxoSmithKline Biologicals, 

Prussia, PA

Catherine Moffit, Vista Health Plans, Sunrise, FL

Kelly Moore, Tennessee Department of Health, 

Nashville, TN

Martin Myers, National Network for Immunization 

Information, Galveston, TX

Thomas Netzer, Merck & Co., Inc., West Point, PA

Timothy Obara, GlaxoSmithKline, Philadelphia, 

PA

Shelly O’Donovan, GSK Biologicals, Philadelphia, 

PA

Jennifer O’Neill, Merck & Co. Inc., McKinney, TX

Kevin O’Neill, Wyeth Vaccines, Collegeville, PA

Paul Offit, Children’s Hospital of Philadelphia, 

Philadelphia, PA

Walter Orenstein, Emory University, Atlanta, GA

Karen Pazol, Emory University, Atlanta, GA

Georges Peter, Brown Medical School, Brookline, 

MA

Diane Peterson, Immunization Action Coalition, 

Saint Paul, MN

Stanley Plotkin, sanofi pasteur, Doylestown, PA

Gregory Poland, Mayo Clinic Foundation, 

Rochester, MN

Mila Prill, Emory University, Atlanta, GA

Jane Quinn, GlaxoSmithKline, Philadelphia, PA

James Ransom, NACCHO, Washington, DC

Mobeen Rathore, University of Florida, 

Jacksonville, FL

Jill Ray, Georgia Chapter AAP, Atlanta, GA

Lyn Redwood, SafeMinds, Tyrone, GA

Margaret Rennels, GlaxoSmithKline, Washington, 

DC

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Mitchell Rothholz, American Pharmacists 

Association, Washington, DC

Matthew Rousculp, Medimmune, Gaithersburg, 

MD

Beth Rowe-West, North Carolina Immunization 

Branch, Raleigh, NC

Patricia Saddier, Merck Research Laboratories, 

North Wales, PA

David Schechter, Merck & Co., Inc., West Point, 

PA

Laurie Schowalter, GlaxoSmithKline, Philadelphia, 

PA

Laura Scott, Ketchum, Washington, DC

Darin Seehafer, sanofi pasteur, Indian Trail, NC

Jina Shah, Novartis, Emeryville, CA

Alan Sievert, American Academy of Pediatrics 

Georgia Chapter, Braselton, GA

Julie Sievert, Merck Vaccine Division, Chicago, IL

Robert Sparks, Vanderbilt University, Nashville, 

TN

Gary Stein, Families Fighting Flu, Falls Church, 

VA

Raymond Strikas, National Vaccine Program 

Office, HHS, Washington, DC

Stacy Stuerke, Merck Vaccine Division, Overland 

Park, KS

Florence Synn, Merck & Co., Inc., North Wales, 

PA

Lynne Sweeney, GlaxoSmithKline, Philadelphia, 

PA

Theodore Tsai, Novartis, Philadelphia, PA

Mariam E. Tucker, Pediatric News, Rockville, MD

Mark Twyman, MedImmune, Gaitherburg, MD

Peter Vigliarolo, Cooney Waters, New York, NY

John Vittas, Families Fighting Flu, Colleyville, TX

Robert Walker, MedImmune Inc., Columbia, SC

Beth Ward, Georgia Division of Public Health, 

Atlanta, GA

Beverly Warden, Constella Group, Rockville, MD

James Wassil, Merck & Co., Inc., West Point, PA

Barbara Watson, Philadelphia Department of Public 

Health, Philadelphia, PA

Deborah Wexler, Immunization Action Coalition, 

St. Paul, MN

Patricia Whitley-Williams, UMDNJ-Robert Wood 

Johnson Medical School, New Brunswick, NJ

Sharon Wible, GSK Biologicals, Philadelphia, PA

Timothy Wighton, GSK Biologicals, Philadelphia, 

PA

Margaret Williams, APCO Worldwide, 

Washington, DC

Carol Wolf, Merck, Houston, TX

Robin Womeodu, Methodist University Hospital, 

Memphis, TN

Eileen Yamanda, California Department of Health 

Services, Richmond, CA

Greg Yoder, Merck & Co., Inc., Peachtree City, 

GA

Laura York, Wyeth, Collegeville, PA

Jennifer Zavolinsky, Every Child By Two, 

Washington, DC

Richard Zimmerman, University of Pittsburgh, 

Pittsburgh, PA

Thomas Zink, Emergent BioSolutions, 

Gaithersburg, MD

Carlos Caduff, University of California at Berkeley, 

CA

Iksung Cho, MedImmune, Inc., Gaithersburg, MD

Connolly Ebhlin, Department of Health and 

Children, Dublin, Ireland

Laura Kigilio, GlaxoSmithKline, Prussia, PA

Christopher Fitzgerald, Department of Health and 

Children, Dublin, Ireland

Hajime Kamiya, Rollins School of Public Health, 

Decatur, GA

Jim Kiely, Department of Health and Children, 

Dublin, Ireland

Cesar Mascarenas Santos, sanofi pasteur, Mexico 

City, Mexico

Monica Naus, BC Centre for Disease Control, 

Vancouver, BC, Canada

Yandong Qiang, Johns Hopkins University, 

Baltimore, MD

Forian Schodel, Merck Research Laboratories, 

North Wales, PA

Anne Elisabeth Schuind, GlaxoSmithKline, Prussia, 

PA

Judith Schindman, sanofi pasteur, Toronto, Ontario, 

Canada

Lifjen Tan, American Medical Association, 

Chicago, IL

Keiko Taya, Infectious Disease Survillance Center, 

Tokyo, Japan

Takehiro Togashi, Sapporo City University, 

Sapporo, Japan

Laura Jean York, Wyeth Vaccines, Collegeville, 

PA

CDC PARTICPANTS

Anne Schuchat, M.D.

Jean Clare Smith, M.D., M.P.H.

Greg Wallace, M.D.

Melinda Wharton, M.D. 

 

STAFF/VENDORS

Sharon Cramer Bell, Writer/Editor

Diane Gaffoglio, Certified Court Reporter

Demetria Gardner, National Immunization Program

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Acronyms

AAP American Academy of Pediatrics

ACIP Advisory Committee on Immunization Practices 

CDC Centers for Disease Control and Prevention 

CMS Centers for Medicare and Medicaid Services

DHHS Department of Health and Human Services 

FDA Food and Drug Administration 

HCUP Healthcare Utilization Project 

HRSA Health Resources and Services Administration 

IOM Institute of Medicine 

ISO Immunization Safety Office

NCHHSTP National Center for HIV, Hepatitis, STD and TB Prevention 

NCIRD National Center for Immunization and Respiratory Diseases 

NIH National Institutes of Health

NVAC National Vaccine Advisory Committee

NVPO National Vaccine Program Office

NVSN New Vaccine Surveillance Network

VAERS Vaccine Adverse Event Reporting System 

VFC Vaccines for Children

VSD Vaccine Safety Datalink

This document has been archived for historical purposes.